Infertility Treatment

Polycystic Ovarian Syndrome

• Ovulation induction is part of patient’s management which aims to achieve development of a single follicle and subsequent ovulation in woman with anovulation
• Please see Polycystic Ovarian Syndrome disease management chart for further information

Hyperprolactinemia

• Treatment is directed towards the cause of hyperprolactinemia
• If pituitary adenoma and extrapituitary tumors are present, these will need to be managed before proceeding with fertility treatment
• Women with clinical evidence of hyperprolactinemia, LH and FSH production is reduced and this can be easily treated with medication
  
  

Polycystic Ovarian Syndrome (PCOS)

Aromatase Inhibitors

• Eg Letrozole, Anastrazole
• Inhibit aromatase which converts androgen to estrogen, thus reducing estrogen levels
  • Increase FSH secretion thereby stimulating ovarian follicle development and maturation
• Consider Letrozole as 1st-line agent for induction of ovulation in anovulatory women with PCOS and with no other factors of infertility to improve ovulation, pregnancy and rates of live births
• Appear comparable to Clomifene based on small clinical trials
  • Studies showed higher live-birth and ovulation rates with Letrozole when compared with Clomifene and failure to ovulate is lower with Letrozole compared with Clomifene
• May be used as an alternative in anovulatory WHO class II patients unresponsive to Clomifene
• Benefits include oral administration, relatively short half-life, potentially higher implantation rates and lower multiple pregnancy rates due to monofollicular ovulation
• Further study is needed to confirm effects on the fetus

Gonadotropins

• May be used as 2nd-line pharmacological therapy in women with PCOS with anovulatory infertility and no other infertility factors who failed 1st-line oral ovulation induction therapy 
• If patients fail to ovulate with Clomifene or in patients who ovulate with Clomifene but have failed to conceive, FSH with or without LH may be given or laparoscopic ovarian drilling with diathermy may be done
• Gonadotropins alone or with Metformin may be used in anovulatory women with Clomifene resistance and with no other factors of infertility to improve ovulation, pregnancy and rates of live births
• Gonadotropin-induced ovulation should only be performed when there are <3 mature follicles and should be canceled if there are >2 mature follicles and patient advised to avoid unprotected intercourse
• Hormonal and sonographic monitoring should be done with gonadotropin therapy to help reduce the chance of multiple gestation and ovarian hyperstimulation

Follicle-Stimulating Hormone (FSH)

• Directly stimulates follicular growth in the ovary
• Available as a variety of formulations that can be derived from recombinant FSH (rFSH) or urinary FSH (uFSH)
  • Eg Follitropin alfa, Follitropin beta, Follitropin delta
    • Follitropin delta has lower serum clearance producing greater exposure and pharmacodynamic response and lesser rate of complications such as ovarian hyperstimulation syndrome (OHSS)
• More suitable to reduce OHSS risk

Luteinizing Hormone (LH)

• Co-administered with recombinant FSH in anovulatory women with low levels of LH and FSH

Human Menopausal Gonadotropin (hMG)

• Available as urinary hMG and urinary highly purified hMG (HP-hMG)
• Purified extract from human postmenopausal urine; contains both FSH and LH
• Directly stimulates the ovaries to induce the development and ovulation of follicles
• Women who are anovulatory and with no other fertility problems may have similar expectant pregnancy rates just like ovulating women of the same age

Insulin-sensitizing Agent

Metformin

• In hyperinsulinemic PCOS, Metformin has been used to restore menstrual cyclicity and induce ovulation with or without the addition of Clomifene
  • May be used alone in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation, pregnancy and live birth rates
• May also be given in combination with Clomifene to anovulatory women with PCOS and BMI of >25 kg/m² who have not responded to Clomifene alone
• Increases the chance of ovulation and pregnancy
  • Concomitant treatment with Metformin may enhance the response to gonadotropin treatment or assisted reproduction therapy

Selective Estrogen Receptor Modulators

Clomifene

• An estrogen antagonist which can induce ovulation by raising the levels of FSH and LH
• Approximately 70% of anovulatory women ovulate after Clomifene treatment
  • Live birth rates after 6 months of treatment with Clomifene range from 15-50%
  • About 7% of pregnancies are twin pregnancies, 0.5% are triplet pregnancies
  • Miscarriage rates have been reported at 13-15%
• Patients who do not respond to Clomifene are more likely to be more insulin-resistant, obese and more hyperandrogenic compared to those who ovulate
  • Failure to ovulate at a dose of 150 mg is considered Clomifene-resistant
• Depending on the clinical practice, Clomifene may be tried for 6-12 cycles; not to be used for >6 months
• Ultrasound (US) monitoring at least for the 1st cycle is needed to adjust the dose to minimize the risk of multiple pregnancy
• There may be an increase in pregnancy rates by adding Clomifene to Metformin, particularly in obese women or those who are Clomifene-resistant, compared with the use of Clomifene alone based on 2 meta-analyses

Tamoxifen

• Anti-estrogen drug widely used in breast cancer treatment which has similar structure and properties to Clomifene
• Pregnancy and ovulation rates have been shown to be similar with Clomifene but combination of both has no advantage

Hypogonadotropic Hypogonadism

Pulsatile GnRH

• Suitable for women with hypothalamic amenorrhea with normal pituitary function in countries where therapy is available
• A small mechanical pump is worn by the woman that delivers a pulse of GnRH every 90 minutes
  • A course of Clomifene therapy may be given before starting treatment with pulsatile GnRH
• Hyperstimulation occurs less often than with hMG and therefore less monitoring is required
• Many women find the pump cumbersome and prefer hMG

Gonadotropin Therapy

• Option in women with hypothalamic amenorrhea or hypogonadotropic anovulation with hypopituitarism who cannot obtain pulsatile GnRH therapy
• hMG, rFSH and uFSH may all be used but treatment with hMG has been reported to be more effective in improving ovulation than FSH alone
  • Gonadotropins with LH activity may be offered for ovulation induction
• Hormonal and sonographic monitoring should be done with gonadotropin therapy to help reduce the chance of multiple gestation and ovarian hyperstimulation

Diminished Ovarian Reserve

GnRH Antagonists

• Associated with shorter treatment length compared to long GnRH agonist protocol

GnRH Agonists

• Equally effective with GnRH antagonists

Mild Stimulation

• Use of Clomifene citrate alone or in combination with gonadotropins is recommended for predicted poor responders
• A meta-analysis has shown no significant difference for clinical pregnancy rates and live birth rates between conventional protocol of agonist and mild protocol of gonadotropins with Clomifene and GnRH antagonist

Recombinant LH

• Higher clinical pregnancy rates were observed with combination of rFSH and rLH

Hyperprolactinemia

Bromocriptine

• Dopamine receptor agonist (D₂) inhibits the release of prolactin
• Prolactin level normalizes in 70-80% of patients given Bromocriptine
  • Tumor size decreases in half of the patients with micro- and macroadenoma
  • Resumption of menses and ovulation in 80-90% of hyperprolactinemic women
• Attempt to reduce neonatal exposure to the drug
  • As soon as pregnancy is confirmed, Bromocriptine should be discontinued
  • 5% of microadenomas and 15-30% of macroadenomas may grow during pregnancy
  • Prolactin levels rise progressively in pregnancy and monitoring of prolactin levels is not useful
  • Regular visual field examination throughout pregnancy is recommended
    • Visual field testing is recommended in patients with macroadenomas
  • Restart Bromocriptine if tumor growth occurs and explain to patient the risks and benefits of treatment
  • Surgical decompression may be done if vision is threatened

Cabergoline

• Useful in patients who are resistant or intolerant to Bromocriptine
  • Fewer side effects than Bromocriptine and can be given 2x/week
• Ergot derivative with high selectivity for D₂ receptors
• 85% of treated women will ovulate and become pregnant if there are no other causes of infertility
• Safety for use in women intending to become pregnant has not been established

Quinagolide

• Pituitary selective D₂ receptor agonist used in cases of Bromocriptine resistance or intolerance

Other Causes of Infertility

Cervical Factors

• Addition of estrogen prior to ovulation may be beneficial but lacks clear clinical value

Endometriosis

• Medical suppressive therapies such as oral contraceptives (OCs) or GnRH agonists are not effective in managing infertility due to endometriosis
  • GnRH agonist suppression plus addback therapy for 3-6 months given before IVF is associated with an improved pregnancy rate
• Please see Endometriosis disease management chart for further information

• It is recommended to do ultrasound between 18 and 22 weeks of gestation to check for congenital structural abnormalities

Intrauterine Insemination (IUI) 

• Sample of washed, prepared, motile sperm is deposited in the uterus just before the release of egg or eggs in a natural or stimulated cycle
  • Higher rates of conception are noted when fresh sperm is used than with frozen-thawed sperm
• Consider IUI as an alternative to vaginal sexual intercourse in the following groups:
  • People using partner or donor sperm who are unable to or find it difficult to have vaginal sexual intercourse (eg clinically diagnosed physical disability, psychosexual problems)
  • Conditions that require specific consideration (eg after sperm washing for HIV-positive men)
  • Cervical factor infertility
  • Same-sex relationships
• IUI, with or without ovarian stimulation, should not be routinely offered to patients with unexplained infertility or mild endometriosis who are having regular unprotected intercourse
• Couples using artificial insemination to conceive should time the procedure around ovulation 
• >50% of women <40 years old will become pregnant within 6 cycles of IUI; about half of those who did not conceive will become pregnant with another 6 cycles 
• Multiple pregnancy is the major risk that may be encountered if ovarian stimulation is used in IUI and cycle is terminated if there are >3 developing follicles

Polycystic Ovarian Syndrome (PCOS)

• Women who have ovulated with Clomifene for 6-12 cycles but have failed to become pregnant should be offered Clomifene-stimulated IUI

Endometriosis

• IUI may be used to manage minimal or mild endometriosis
  • Couples should be informed that ovarian stimulation increases pregnancy rates but effectiveness of unstimulated IUI is uncertain; still, pregnancy rate is low after controlled ovarian hyperstimulation-IUI in patients with endometriosis
• Done for 6 cycles with US monitoring

Unexplained Infertility

• Multifollicular development is induced using Clomifene or gonadotropins (eg FSH)
• IUI with ovarian stimulation using Clomifene citrate is the primary treatment for couples with unexplained infertility
  • Has been shown to be superior to expectant management and IUI without stimulation in terms of live-birthrate outcome
• IUI with ovarian stimulation using Letrozole may be used as an alternative regimen for couples with unexplained infertility
  • Several trials have shown no significant difference in pregnancy rates or multiple-gestation pregnancy rate between IUI with Letrozole and IUI with Clomifene
• IUI with ovarian stimulation with gonadotropin may be an alternative for couples with unexplained infertility
  • Associated with higher pregnancy rate per cycle and higher multiple pregnancy rate per cycle than IUI with Clomifene or Letrozole
• 3-6 cycles are recommended

In vitro Fertilization (IVF)

• Patients with unexplained infertility, mild endometriosis, or mild male factor infertility who are having regular unprotected sexual intercourse should try to conceive for 2 years (1 year before fertility investigations included) before considering IVF
• Indications for IVF include severe tubal dysfunction, pelvic anatomy distortion, endometriosis unsuccessfully treated with surgery or medications, unexplained infertility, unsuccessful initial treatment for infertility (eg PCOS, hypogonadotropic hypogonadism), and male factor infertility
• The chance of a live birth after IVF is inversely related to the woman's age and the number of failed treatment cycles
  • IVF is more effective in patients who had been pregnant and/or had a live birth  
  • May also optimize outcomes by removing hydrosalpinges before IVF
• Immunotherapies (eg granulocyte or granulocyte/macrophage colony-stimulating factor, seminal plasma insemination, IV immunoglobulin, Adalimumab, Tacrolimus, Aspirin, corticosteroids) are either not associated with improved outcome of live birth in IVF or have not been sufficiently studied thus patients should be informed of the risks and benefits associated with its use 
• Normally, a full cycle, with or without intracytoplasmic sperm injection (ICSI), is made up of 1 episode of ovarian stimulation and the transfer of any resultant fresh and frozen embryo/s
• IVF is done up to 3 cycles in women who are <40 years who have not conceived after 2 years of regular unprotected intercourse or 12 cycles of artificial insemination; may also be done up to 1 cycle in women aged 40-42 years who have not conceived after 2 years of regular unprotected intercourse or 12 cycles of artificial insemination provided that they (1) have never had IVF, (2) no evidence of ovarian reserve being low and (3) were informed of the additional implications of IVF and pregnancy at this age
• HIV, hepatitis B and C tests are done prior to IVF to avoid passing these infections to the offspring or to other people and when found to be positive, counseling and treatment are given
• Several steps are followed during IVF cycle: Ovarian stimulation, follicular aspiration, oocyte classification, sperm preparation, oocyte insemination, embryo culture and embryo transfer

Ovarian Stimulation

• Aims to attain a reasonable number of follicles and oocytes by extra ovarian stimulation while minimizing risk of complications such as OHSS
• The lowest effective dose and length of use should be used for ovarian stimulation agents 
• Ovarian response is monitored using US and serum estradiol level determination; serum LH level may also be requested
• Clomifene
  • Protocol consists of 5-7 days treatment
  • Disadvantages: Low oocyte yield, frequent LH surges, high cancellation rate and low pregnancy rate

• Clomifene and hMG
  • Combination may increase the number of recruited follicles
  • Disadvantages: Spontaneous LH surge, high cancellation rate and premature luteinization

• Clomifene, gonadotropins and GnRH antagonists
  • Based on retrospective controlled study, the combination may increase pregnancy rate comparable to conventional GnRH agonist long-term protocol, however the ideal protocol for the combination is not yet defined

• Gonadotropins
  • Use either urinary or recombinant gonadotropins
    • Recombinant products may be an option for patients with increased risk of complications (eg OHSS)
  • Individualize starting dose based on factors that predict success (eg age, BMI, presence of PCOS), ovarian reserve; FSH dose should not be >450 IU/day
  • Low-dose gonadotropins (≤150 IU/day) with or without oral agents (ie mild ovarian stimulation protocol) may be considered for patients who are poor responders because of comparable low rates of pregnancy and lower costs when compared with conventional IVF stimulation protocols 
  • Gonadotropins in combination with aromatase inhibitors are new ovarian stimulants for IVF in women with breast cancer
  • Disadvantage: Spontaneous LH surge

• GnRH agonists
  • Offered to women with low risk of OHSS 
  • Short-term protocol takes advantage of the flare-up of serum gonadotropins during follicular recruitment phase and the subsequent down-regulation of pituitary gland
    • May be modified by pretreatment with progestogens during the luteal phase of the cycle preceding IVF
  • Ultra-short protocol involves GnRH agonist administration in the early follicular phase and stopping it after 4-5 days
    • Relies on the strategy that the initial administration will lead to slight, but prolonged, suppression of exogenous LH surge
  • Long-term protocol induces pituitary and ovarian desensitization in the early follicular or midluteal phase of the cycle preceding the planned IVF
    • Recommended over short or ultra-short protocol due to higher efficacy
  • Combination of Norethisterone acetate or OC with GnRH agonist is effective in preventing formation of ovarian cyst; the chance of having a live birth is not affected by pretreatment with a progestogen or an OC 
  • GnRH agonists in combination with gonadotropin stimulation produce higher pregnancy rates when compared to gonadotropins used alone
  • Use of GnRH agonist may require luteal phase support
  • Potential risks and disadvantages: OHSS risk secondary to excessively high estradiol levels, increased multiple pregnancy, costly due to increased requirements of gonadotropins and longer duration of therapy

• GnRH antagonists
  • Eg Cetrorelix, Ganirelix
  • Block LH surge at the preovulatory period, hence premature luteinization does not occur
  • Monitoring of LH and progesterone may be helpful for optimal guidance
  • Preferred over GnRH agonists in women with PCOS undergoing IVF to reduce duration of stimulation, total gonadotropin dose and incidence of OHSS
  • Advantages: Shorter treatment protocol without initial flare-up effect, reduced overall cost due to lower amount of total gonadotropins needed for ovulation stimulation, shorter period of gonadotropin stimulation, reduced risk of severe OHSS, avoidance of cyst formation
  • Administered when the largest follicle reaches 14 mm or when serum LH levels >10 mIU/mL
  • Cetrorelix, a 3rd-generation GnRH antagonist is used for ovarian stimulation
    • 2 preparations are available for optimal tailoring to individual patients’ needs
  • May also use Ganirelix for ovarian stimulation
  • Multiple-dose protocol involves daily injections of low-dose GnRH antagonists from day 6 of ovarian stimulation
    • In the presence of premature LH surge, Cetrorelix 0.25 mg is started earlier
    • Cetrorelix 3 mg is recommended provided that Cetrorelix 0.25 mg was given <4 days
    • Patients who show poor response may benefit from the addition of recombinant luteinizing hormone (rLH) in multiple-dose protocol, or may choose other alternative stimulation protocol
  • Single-dose protocol involves administration of GnRH antagonists during late follicular phase
    • Addition of rLH or the use of hMG is not necessary

• Human chorionic gonadotropin (hCG)
  • Used to induce final follicular maturation and to trigger ovulation
  • Recombinant hCG provides similar outcome with urinary preparation in terms of oocyte numbers and pregnancy rates, higher progesterone levels in the luteal phase, and reduced incidence of local injection site reactions
  • Lowest doses should be used to trigger final oocyte maturation in women with PCOS undergoing IVF to reduce incidence of OHSS 

• hMG
  • May be an option for ovarian stimulation

• Trophic hormones and related synthetic drugs
  • Eg Corifollitropin alfa
  • Used in combination with a GnRH antagonist for development of multiple follicles in women in an assisted reproduction techniques (ART) program
  • Effectively replaces the first 7 daily doses of rFSH in controlled ovarian stimulation (COS) cycles

Follicular Aspiration

• Transvaginal follicular aspiration guided by US is done 35-36 hours after hCG administration

Oocyte Classification

• Important step for IVF success
• Oocytes are graded based on the corona-cumulus complex appearance

Oocyte Insemination and Embryo Culture

• Each oocyte is inseminated with 50,000-100,000 motile, morphologically normal sperms
• Ideally, the presence of 2 pronuclei and extrusion of 2nd polar body are the criteria required to determine fertilization; fertilization usually occurs 12-20 hours after insemination
• Embryos or fertilized oocytes are transferred into growth media and are incubated

Embryo Transfer

• Embryos are transferred transcervically under transabdominal US
• For women <37 years: Use 1 embryo transfer in 1st full cycle; 1 embryo if ≥1 top-quality embryos are available or 2 embryos if with no top-quality embryos in the 2nd cycle; and no more than 2 embryos in the 3rd cycle
• For women aged 37-39 years: Use 1 embryo transfer in 1st and 2nd cycles if ≥1 top-quality embryos are available; if no top-quality embryos, consider 2; and no more than 2 embryos in the 3rd cycle
• For women aged 40-42 years: Consider a double embryo transfer
• Maximum of 2 embryo transfers per cycle; 1 embryo if a top-quality blastocyte is available
  • Risk of multiple gestation is associated with double embryo transfer

Luteal Support

• Progesterone is recommended for luteal phase support following IVF/ICSI 
• During the luteal phase, progesterone is administered 72 hours after oocyte aspiration and continued for about 2 weeks; not necessary beyond 8 weeks of gestation
  • Several routes of progesterone delivery are suggested (oral, intramuscular and vaginal) but vaginal route offers several advantages
• Avoid routinely offering hCG for luteal support as it increases likelihood for OHSS

Cryopreservation

• May be done to good-quality embryos remaining after the embryo transfer for future use
  • Increasing evidence shows that outcomes of pregnancy with cryopreserved embryos fertilized in vitro are better than for fresh embryo transfers
• It makes future assisted reproductive technologies cycles simpler, less invasive and less expensive compared to the initial IVF cycle
• Option for couples prior to starting chemotherapy or radiotherapy that will likely make them infertile
  • In preserving fertility in people with cancer, sperm, oocytes or embryos may be cryopreserved
• Offer to men and adolescent boys prior to treatment for cancer that will make them infertile
• Offer oocyte/embryo cryopreservation to women and adolescent girls prior to cancer treatment that will make them infertile if well enough for ovarian stimulation and egg collection without making their condition worse and if there is enough time before they start the cancer treatment
• Initial cryopreservation period is 10 years; can go beyond this for men who remain at risk for infertility

Gamete Intrafallopian Transfer (GIFT)

• Gametes are transferred to the woman’s fallopian tubes rather than her uterus and fertilization occurs in the fallopian tubes rather than in the laboratory
• Alternative in women who have normal fallopian tubes
• Use is limited because fertilization cannot be confirmed and there is insufficient evidence to recommend use in couples with unexplained fertility problem and male fertility problems in preference to IVF

Zygote Intrafallopian Transfer (ZIFT)

• Fertilization happens in the laboratory then the zygote is transferred to the fallopian tube by laparoscopy
• Use is limited as there is insufficient evidence to recommend use in couples with unexplained fertility problem and male fertility problems in preference to IVF

Oocyte Donation

• Considered in patients with:
  • Premature ovarian failure [gonadal dysgenesis (eg Turner syndrome), following chemotherapy or radiotherapy]
  • Bilateral oophorectomy
  • Certain cases of failure with IVF treatment
  • Genetic disorder

Risks of Assisted Reproduction

• Ovarian hyperstimulation syndrome 
• Surgical complication from laparoscopy (eg bleeding, infection, or damage to bowel, bladder, or blood vessel)
• Multiple pregnancy
• Psychological stress
• Preterm and low birth weight infants in singleton pregnancies