Infertility

1. Infertility Dr. Bahador Mirrahimi PharmD, IBSCP, Assistant Professor SBMU.

2. PATHOPHYSIOLOGY AND DIAGNOSIS • Current primary infertility estimated by National Health Survey (NHS) was 2.8% and by National Infertility Survey (NIS) 3.4%. Tehran study and NIS estimated the prevalence of lifetime primary infertility to be 21.9% and 24.9%, respectively.(2009) •  the prevalence of primary infertility to be 20.2% in Iran.(2011) • Infertility is defined as the inability to conceive after one year of unprotected intercourse. • The definition is based upon the observation that roughly 85% of couples with normal fertility will achieve pregnancy within one year.

3. PATHOPHYSIOLOGY AND DIAGNOSIS • factors affect infertility rates: • Advancingmaternal age appears to be a prominent influence • chromosomal abnormalities • abortion rates • Male fertilityis impacted by age as well, with a documented decline afterage 35

4. General Risk Factors • Lifestyle factors such as tobacco or illicit drug use and caffeine intake are known contributors to infertility. • moderate use of one to two cups of coffee or equivalent appears to have minimal impact. • Occupational and environmental exposures: • pesticides, • heavy metals • toxins such as organic solvents used in dry cleaning and printing

5. TREATMENT APPROACHES • Regardless of the treatment approach, all couples pursuing pregnancy are encouraged to avoid tobacco, alcohol, and illicit substances, and limit caffeineintake. • The female partner should take a daily supplement containing 400 to 800 mcg of folic acid to reduce the risk of neural tube defects once pregnancy occurs. • Any chronic medications must be evaluated for potential safety issues during pregnancy and discontinued or switched to a safer alternative • Patients are encouraged to achieve and maintain a normal weight, which is associated with a lower risk for failed treatment cycles and pregnancy loss. • Obesity is another feature associated with PCOS. • extremely low body weight and excessive exercise

6. Female Factor InfertilityOVULATORY DYSFUNCTION • 40% of femalefactor infertility • regular menstrualcycles of 22 to 35 days with premenstrual symptoms ordysmenorrhea • regulated through complex feedbackmechanisms within the hypothalamic-pituitary-ovarian axis • thyroid dysfunction • hyperprolactinemia, • polycystic ovary syndrome (PCOS)

7. methods are available to further define ovulatoryfunction. • Basal body temperature monitoring • measurement of body temperature every morning • body temperatureof approximately 0.3c to 0.6 after ovulation • home ovulation test kits that detect urinary LH. • A positive test = ovulation will occur in an average of 24 hours • Measured day 12 to 16 of cycle

8. Anovulation associated with hyperprolactinemia • treated with oral dopamine agonists such as bromocriptine. • Prolactin levels should normalize after 4 weeks of treatment in most patients, • 80% reporting successful ovulation once this occurs.

9. Assessment of ovarian reserve • recommended for women older than age 35 • measurement of basal levels of serum FSH and/or estradiol on day 3 of the menstrual cycle

10. Impaired cervicalmucus production • Cervical mucus increases in volume and becomes thinner as the follicular phase progresses to facilitate spermtransport at ovulation. • The use of the oral mucolytic guaifenesin in doses of 600 mg twice daily or 200 mg three times daily is a popular to improve the quality of cervical mucus. However, there are few data to support its impact on pregnancy rates.

11. Male Factor Infertility • male factors are present in up to 40%. • Impaired sperm production: • testicular trauma, • cryptorchidism, • radiation, • Antiandrogen medications. • Varicoceles, • Sperm transport defects: • Erectile dysfunction, • retrograde ejaculation, • obstruction of the vasdeferens or epididymis. • Medications such as antidepressants or antihypertensives can worsen libido and ejaculatory function • Weight may play a role in male fertility due to elevated estrogen and lower testosterone levels

12. Ovulation Induction/Controlled Ovarian Stimulation • There are two general treatment strategies that focus on ovulation: • “ovulation induction” (OI) • Ovulation induction is pursued in patients who are not ovulating • “controlled ovarian stimulation” (COS). • for women who are already having ovulatory cycles but are still experiencing infertility • Both treatments incorporates many of the same medications.

13. OVULATION INDUCTION Anovulatory women with adequate ovarian reserve and no other treatable cause are candidates for OI. mimic the hormonal patterns of the normal menstrual cycle. The goal of OI is the development of a single dominant follicle

14. OVULATION INDUCTION • The choice of medications for OI is dictated by hypothalamic-pituitary- ovarian function. • With adequate hypothalamic function, an oral regimen of Clomiphene citrate which exhibits estrogen agonist and antagonist activity, is often utilized first line. • Clomiphene citrate inhibits estrogen binding in the hypothalamus to stimulate release of GnRHand pituitary gonadotropins and induce ovarian follicular development. • Oral aromatase inhibitors are not approved by the US Food and Drug Administration (FDA) for OI, but also increase release of GnRH and pituitary gonadotropins through an estrogen antagonist effect

15. OVULATION INDUCTION • If hypothalamic or pituitary dysfunction is detected or if oral regimens are not successful, injectable gonadotropins are administered. • The most common gonadotropin regimens use FSH administered alone or in combination with LH: • “step-up” protocol represents the natural progression of gonadotropin release during the menstrual cycle. Initial daily injections of 50 to 75 international units are increased in increments of 37.5 international units as necessary for a follicular response • “step-down” protocol uses higher initial daily doses of 150 international units until a dominant follicle is apparent on ultrasound. The daily dose is then decreased incrementally until ovulation is triggered.

16. OVULATION INDUCTION • An injection of human chorionic gonadotropin (hCG) is administered during the OI process to simulate the LH surge. • The timing is based on the growth of ovarian follicles monitored with intravaginal ultrasound. As one follicle matures to 16 to 18mm in diameter. • a single dose of hCG is injected and ovulation is expected to occur within 24 to 48 hours. • This is timed with natural intercourse or other infertility procedures to achieve pregnancy.

17. Gonadotropins for Ovulation Induction/Controlled Ovarian Hyperstimulation

18. CONTROLLED OVARIAN STIMULATION • The oral and injectable medications intended to develop multiple ovarian follicles. • Clomiphene citrate is the most common initial choice because of the convenience and low cost of an oral regimen and the widespread experience with its use.

19. CLOMIPHENE CITRATE

20. CLOMIPHENE CITRATE • The typical initial dosing regimen for CC is 50 mg once daily for 5 days starting on day 5 of the menstrual cycle. • Some clinicians prefer initiating therapy on day 3, although there is no clinical advantage • Ovulation typically occurs 5 to 12 days after the fifth dose is taken. • If ovulation is documented but pregnancy does not occur, the same dose of CC is used in future cycles. • If ovulation does not occur, then the dose is increased by 50 mg with each subsequent cycle. • Although the product labeling does not recommend doses above 100 mg per day, CC doses as high as 250 mg have been described in the literature. • Alternative medication approaches are typically recommended if daily doses of 150 mg are not successful.1

21. CLOMIPHENE CITRATE • associated with per-cycle pregnancy rates ranging from 3% to 8%. • It is frequently combined with intrauterine insemination (IUI) which introduces a processed semen sample directly to the uterus via a catheter placed through the cervix. • using a urinary ovulation home test kit to identify the natural LH surge or injecting hCG to trigger ovulation and planning the IUI 24 to 36 hours later • Multiple treatment cycles with the combination of CC and IUI are commonly pursued, but there is little evidence for effectiveness beyond six attempts. • Aromatase inhibitors or gonadotropins are suitable alternatives to combine with IUI.

22. Adverse effects of clomiphene • Vasomotor symptoms (10% to 20%) • night sweats, hot flashes, and flushes. • headache, • irritability, • mood swings, • Nausea • Long-term concerns • multiple gestation in 8% to 10% • Minimal risk of increased rates of ovarian cancer in women exposed to more than 12 cycles

23. AROMATASE INHIBITORS • The aromatase inhibitors letrozole and anastrazole are emerging as oral alternatives to CC, although they are not FDA-labeled for ovulation induction or COS. • Aromatase is an enzyme that converts androstenedione to estrone and testosterone to estradiol.

24. AROMATASE INHIBITORS • The recommended administration schedule is similar to clomiphene: once daily for 5 days beginning on cycle days 3 to 5. • letrozole 2.5 or 5 mg • anastrozole 1 mg • There is a reduced incidence of multiple gestation pregnancy compared with CC because of the development of fewer follicles • Pregnancy rates with letrozole appear to be similar to clomiphene.

25. AROMATASE INHIBITORS • Adverse effects: • Aromatase inhibitors do not affect cervical mucus or endometrial development, but this finding has not translated into improved pregnancy outcomes in clinical studies. • Initial concerns of the teratogenic potential of aromatase inhibition during fetal development prompted a warning against use in premenopausal women who are or may become pregnant to be included in the product labeling. • surveillance studies of letrozole cycles do not demonstrate higher rates of congenital malformations as compared to CC. • The early timing of administration in the cycle reduces the risk of fetal exposure.

26. Male Factor Infertility • Interventions to improve sperm parameters typically target the underlying cause if possible, such as treatment of hyperprolactinemia or supplementation with testosterone. • Clomiphenimproves sperm concentrations in men with hypogonadotropichypogonadism by stimulating hypothalamic release of GnRH. • FDA-labeled for use in women only. • Various regimens of injectable gonadotropins (FSH, LH, or hCG) also improves pregnancy rates. • Antioxidants such as vitamin C, vitamin E, folic acid, zinc, selenium, and l-carnitine are reported to counteract negative effects from oxidative stress on sperm. • Insemination by bypassing the cervix and placing the sperm closer to the fallopian tubes near the time of ovulation can overcome lower sperm counts and motility issues.

27. Assisted Reproductive Technology(ART) • number of cycles increasing from just below 88,000 in 1999 to more than 148,000 in 2008. This represents an estimated 1% of live births • Of the 104,673 fresh, non-donor ART cycles in 2008, 37% resulted in a pregnancy and 30% in a live birth. • infants born from multiple gestation pregnancies, which make up approximately 30% of pregnancies from ART, may experience health complications as a result of preterm birth and low birth weight. • The data regarding birth defects remain conflicting • infertility itself has been linked to an increased risk for birth defects

28. INDICATIONS: • both female and male factor infertility: • For women with adequate ovarian reserve COS can be combined with ART procedures • additional male factors and/or implantation. • female structural factors.

30. PROCEDURES

31. PROCEDURES • Intracytoplasmic sperm injection (ICSI): • the injection of sperm directly into the oocyte during the fertilization process • severe sperm dysfunction • gamete intrafallopian transfer(GIFT): • retrieved oocytes are transferred with the sperm to the fallopian tube to allow for natural fertilization • zygote intrafallopian transfer(ZIFT): • retrieved oocytes are transferred with the sperm to the fallopian tube to allow for natural fertilization • slightly lower live birth rates than IVF (21% and 18% vs. 34%)

32. Description of Select Infertility Procedures

33. GONADOTROPINS • If oral agents are unsuccessful, COS can be attempted with injectable gonadotropins including FSH alone or in combination with LH. • The per-cycle conception rates are higher than that of CC or aromatase inhibitors in most studies. • A standard protocol involves daily injections of FSH or a combination of FSH and LH to stimulate follicular development. • Human chorionic gonadotropin is administered as a single injection to finalize follicular development and induce ovulation.

34. In Vitro Fertilization Cycle

35. STAGE ONE: CONTROLLED OVARIAN STIMULATION • Oral Contraceptives: • Many protocols start with the administration of oral contraceptives for up to 28 days in thepreceding menstrual cycle. • This is particularly pertinent in women who have irregular or long menstrual cycles. • Acts to suppress any ovarian cysts that can develop in previous COS regimens and thus delay subsequent treatment cycles. • Gonadotropin-Releasing Hormone Analogs • Most protocols use medications to limit the influence of any endogenous hormone levels • The depot formulationsused for endometriosis or hormone-dependent cancers are notideal for IVF. • The prolonged pituitary suppression is associatedwith a need for higher doses and longer duration of gonadotropinadministration for COS

36. Gonadotropin-Releasing Hormone Analogs Treatment protocols are identified by the timing of GnRH agonist administration.

37. Gonadotropin Releasing Hormone Analogs for In Vitro Fertilization

38. Gonadotropin-Releasing Hormone Analogs • In a traditional “long” protocol, a GnRH agonist is initiated during the follicular or luteal phase of the preceding menstrual cycle (day 21-23). • Once gonadotropins are initiated, the GnRH agonist is continued at half the daily dose until ovulation is stimulated. • If an oral contraceptive is used for pretreatment, the GnRH agonist is often initiated within the last week of the contraceptive regimen. • In a “short” protocol, aGnRH agonist is administered in conjunction with the gonadotropins for the stimulation cycle (day 2-3). • the flare, or initial increase in gonadotropin production, aids in the initial recruitment and development of follicles.

39. Gonadotropin-Releasing Hormone Analogs • Amore recent trend is the use of the GnRH antagonists instead of agonists. Interestingly, cetrorelix and ganirelixare FDA-labeled for use with ART, whereas the GnRH agonists are not! • The immediate suppression of gonadotropin secretion allows for a shorter duration of administration • the lack of a FSH and LH flare reduces the incidence of ovarian cysts that can occur with the GnRH agonists. • either a higher dose single injection or a lower dose daily injection that is continued until ovulation is triggered. • Ganirelix is administered as a daily 250-mcg subcutaneous injection. • cetrorelixis either a dailysubcutaneous injection of 0.25 mg or a single 3-mg dose.

40. Gonadotropins • A common starting dose in fixed-dose protocols is 150 to 225 international units daily, with further dose adjustments made based on the status of the developing follicles. • Treatment may continue for 7 to 12 days, although longer courses may be necessary depending on follicular response. • If subsequent cycles are needed, the initial treatment doses are chosen based on the stimulation achieved in the first cycle.

41. Chorionic Gonadotropin:OOCYTE RETRIEVAL • Many centers schedule oocyte retrieval between 34 and 36 hours after chorionic gonadotropin is injected. • The urinary hCG product is administered as a single intramuscular injection of 5,000 to 10,000 international units • The dose of the recombinant product is 250 mcg injected subcutaneously • A single dose of a GnRH agonist is an alternate method of triggering LH release

42. LUTEAL PHASE SUPPORTProgesterone • The disruption of follicles during the oocyte retrieval process delays production of progesterone, necessitating supplementation. • The intramuscular injection of progesterone in oil in a daily dose of 50 mg was the first method used for supplementation and continues to be widely used. • Intramuscular injection of a progesterone derivative, 17-α- hydroxyprogesteronecaproate (proluton), was viewed as a potential alternative requiring less frequent administration. • Vaginal progesterone preparations have gained popularity for luteal phase support due to ease of administration and the avoidance of injection-site reactions. • The vaginal preparations are associated with local irritation and vaginal discharge (rectal use) • Progesterone is administered daily until a pregnancy test is performed and continued until at least 7 to 9 weeks gestation.

43. Amigo study We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies.