1. Medications Used with Infertility Treatment
E.Naghshineh M.D
OB& GYN specialist / Infertility fellowship
Isfahan university of medical sciences

2. Medications Used with Infertility Treatment
Prescription drugs can be useful when treating infertility issues. These medications are forms of reproductive hormones that stimulate ovaries into producing and releasing eggs.
Clomiphene Citrate / Clomid
Letrozol
Gonadotropins
Human Chorionic Gonadotropin
GnRH Antagonists
GnRH Agonists
Progesterone

3. Clomiphene Citrate / Clomid
Causes release of high amounts of FSH, which initiates growth of ovarian follicles
Taken orally for 5 days during early menstrual cycle (2-5 th day)
Should have an ultrasound prior to using these medications
Most common side effects : mood changes, hot flashes, minor visual disturbances, headaches, irritability and anxiety, vaginal dryness or thinning of endometrial lining

4. Clomiphene Citrate / Clomid
Side effects are temporary and subside once clomid is stopped Ovarian cysts may develop and remain for 4-6 weeks once a woman stops taking clomid, but these cysts are usually harmless
Higher multiple birth rate: 5-10 percent
In most cases: twins
Not been shown to cause the development of birth defects

5. Letrozol (femara)
Clomiphene citrate: drug of first choice for either ovulation induction or superovulation clomiphene citrate lasts for a long time in the body and may therefore have an adverse effect on the cervical mucus and uterine lining
Some patients, such as PCOS do not respond well to clomiphene citrate
Letrozole widely used in women with breast cancer, aromatase inhibitors
Letrozole inhibiting aromatase thereby suppressing estrogen production
Compared with clomiphene citrate, letrozole is associated with a thicker uterine lining and a lower miscarriage rate

6. Letrozole 2013 meeting of ASRM, results of PPCOS study
Ovulation rate superior with letrozole (61.7%) than clomid (48.3%)
Cumulative live birth rate higher with letrozole (27.5%) than clomid (19.5%)
Live birth benefit was higher in obese women (BMI≥35)
Letrozole was equal or superior to Clomid at all BMI groups
There was no difference in:
- Risk for pregnancy loss (letrozole 31.8% vs Clomid 28.2%)
- Multiple pregnancy rates (all twins) (letrozole 3.2% vs Clomid 7.4%)
- Number of serious adverse events

7. Letrozole and birth defects
A study: ASRM in 2005, 4.7% serious birth defects in letrozole use, in control babies 1.8% . birth defects were 3 times more likely to occur with letrozole.
Novartis sent a letter to fertility physicians stating: “Femara is contraindicated in women with premenopausal endocrine status, in pregnancy and lactation due to potential for maternal and fetal toxicity and fetal malformations”.
The Canadian study: major birth defect rate in letrozole group 1.2% and in Clomid group 3.0%
In United States, labeling of letrozole already warned that it had been associated with birth defects. Novartis has never sought FDA approval to market letrozole as a fertility medication and was clearly concerned about their liability if given in pregnancy.

8. Letrozole
Letrozole is metabolized rapidly in body, not thought to have significant levels in blood or tissues for a prolonged period of time
In PCOS II study: no difference in rate of birth defects between letrozole and Clomid
Letrozole side effects:
-reduce estrogen levels, treatment duration for letrozole is only 5days
-Hot flashes, Headaches, Breast tenderness
No increased risk of miscarriage or a decrease in miscarriage risk
Pregnancy Category: D

9. Gonadotropins Stimulate ovaries to produce multiple eggs
FSH and LH are known as gonadotropins
Commercially produced gonadotropins are derived from two sources: biological or manufactured
Biological products: over 30 years, often referred to as HMG, extracted from the urine of postmenopausal women
Manufactured products: contain only FSH
Both safe and effective

10. Gonadotropins Manufactured products : administered by SC
Biological products : administered by IM
Purity of manufactured gonadotropins: use lower doses for a shorter duration of time compared to biological products
Side effects: headache, breast pain, OHSS
Manufactured products: fewer injection-site related side effects, such as pain, redness, itching or swelling

11. Commerical names FSH: Gonal-f, Follistim, Fostimon, Cinnal-f
HMG: Menopur, Menogon, Merional

12. Pergoveris
Contains 2 medications: follitropin alfa (synthetic version of FSH,150 IU) and lutropin alfa (synthetic version of LH, 75 IU)
Contents of a single vial, injected subcutaneously, once daily

13. Elonva
Corifollitropin alfa, 100 or 150 micrograms, pre-filled syringe in 0.5 ml solution for injection
Corifollitropin alfa is a glycoprotein produced in chinese hamster ovary cells by recombinant DNA technology
Elonva is indicated for COH in combination with a GnRH antagonist for development of multiple follicles in women participating in an ART program

14. Elonva Dose of Elonva is based on weight and age
A single 100-microgram:
weigh less than or equal to 60 kg and 36 years of age or younger
- A single 150-microgram:
weigh more than 60 kg, regardless of age
weigh 50 kg or more and older than 36 years of age

15. Elonva
Single SC injection, preferably in abdominal wall, during early follicular phase of menstrual cycle
GnRH antagonist should be started on stimulation day 5-6 depending on ovarian response, i.e. number and size of growing follicles
Seven days after injection with Elonva on stimulation day 1, COS treatment may be continued with daily injections of recombinant FSH until criterion for triggering final oocyte maturation (3 follicles ≥ 17 mm) has been reached
A single injection of 5,000-10,000 IU hCG administered to induce final oocyte maturation

16. Human Chorionic Gonadotropin (hCG)
hCG: a hormone helps to mature eggs and stimulate ovulation, a hormone produced by the placenta after implantation
Two sources: biological or manufactured
Pregnyl, Novarel, Ovidrel
Usual adult dose for ovulation induction:
-hCG: ,000 units, IM
-r-hCG: 250 mcg, SC

17. Ovitrelle
Ovitrelle 250 micrograms/0.5 mL solution for injection in pre-filled syringe
Equivalent to approximately 6,500 IU
Recombinant human chorionic gonadotropin, r-hCG produced in chinese hamster ovary cells by recombinant DNA technology
Maximum dose: 250 micrograms

18. GnRH Antagonists
GnRH is a hormone hypothalamus gland produces that controls pituitary gland’s production and release of LH and FSH.
As part of an infertility treatment regimen, such as IVF, GnRH Antagonist medications block effect of GnRH on pituitary gland, natural ovulation is prevented , allows timing of ovulation to be better predicted and coordinated with procedures such as egg retrieval
Administration: injection SC, once daily during mid to late follicular phase
Side effects: abdominal pain, nausea, headache, vaginal bleeding and injection site reactions (redness or swelling), OHSS

19. Cetrotide
Cetrorelix acetate, a synthetic decapeptide with GnRH antagonistic activity
Cetrotide mg is a sterile lyophilized powder intended for SC injection after reconstitution with sterile water for injection
Inhibition of premature LH surges in women undergoing COH
Administered SC, once daily during early to mid follicular phase, on stimulation day 5 or 6 and continued daily until the day of hCG administration

20. Orgalutran Orgalutran 0.25 mg/0.5 ml solution for injection
Ganirelix , a synthetic decapeptide with high antagonistic activity to GnRH
Prevention of premature LH surges in women undergoing COH for ART
Starting day of orgalutran is depending on ovarian response, number and size of growing follicles and amount of circulating oestradiol
The start of orgalutran may be delayed in absence of follicular growth, although clinical experience is based on starting orgalutran on day 5-6 of stimulation

21. Orgalutran
Orgalutran and FSH should be administered approximately at same time, preparations should not be mixed, different injection sites
Daily continued up to day that sufficient follicles of adequate size
Time between last Orgalutran injection and hCG injection should not exceed 30 hours, as otherwise a premature LH surge may occur
Administered SC, preferably in upper leg, injection site should be varied to prevent lipoatrophy
Very Common side effect: Local skin reaction at site of injection (predominantly redness, with or without swelling)

22. GnRH Agonists
Fertility medicine, treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children
Injections into fat, implants placed into fat, nasal sprays
Side effects: hot flashes, sexual dysfunction, vaginal atrophy, osteoporosis, infertility, diminished sex-specific physical characteristics
The most well-known and widely used GnRH analogue is leuprorelin (brand name Lupron)

23. GnRH Agonists
Suppression of spontaneous ovulation as part of COH, after GnRH agonists induced a state of hypoestrogenism, exogenous FSH given to stimulate ovarian follicle, followed by hCG to trigger oocyte release
GnRH agonists routinely used are: buserelin, leuprorelin, nafarelin, and triptorelin
Final maturation induction after having performed COH in GnRH antagonist cycles
Women of reproductive age, undergo cytotoxic chemotherapy pretreated with GnRH agonists to reduce the risk of oocyte loss and preserve ovarian function

24. GnRH Agonists
Injectables ( daily, monthly, and quarterly), implants (one month to a year), intranassally
Short-acting injection (once per day): buserelin, leuprorelin, triptorelin
Long-acting depot injection or injected pellet (once every one to six months): leuprorelin, triptorelin
Injected implant (once every one to three months): buserelin, goserelin, leuprorelin
Surgically implanted pellet (once per year): histrelin, leuprorelin
Nasal spray (two to three times per day): buserelin, nafarelin

25. Progesterone
Administration: injection and intravaginal gel or suppository
Produced primarily by ovaries, rise sharply shortly after ovulation, preparing inner lining of uterus to receive a fertilized egg
If egg has not been fertilized, ovaries stop producing progesterone and menses begins within 24 to 48 hours
If fertilization occurs, ovaries continue to produce progesterone, which is important in maintaining the pregnancy
Supplemental administration of progesterone:
- some women do not produce sufficient progesterone , may have
difficulty conceiving
- Women undergoing ART procedures

26. Progesterone
Usually started a few days after ovulation and is continued until either menses occurs or pregnancy is confirmed
In pregnancy: progesterone may be continued for weeks. By this time, the placenta is producing sufficient amounts of progesterone for the remainder of the pregnancy.
Adverse effects: nausea, constipation, breast enlargement and tenderness, headache, drowsiness, vaginal discharge, joint discomfort and depression, fluid retention
Patients with certain medical conditions such as epilepsy, migraine headaches, asthma and cardiac or renal impairment require close observation

27. Visanne Dienogest, 2mg Tablet
Helps to reduce pelvic pain experienced by women with endometriosis
Taken by mouth once daily, should be taken at same time every day
Can be started on any day of menstrual cycle
Must be taken continuously without regard to vaginal bleeding, after first pack has been finished next should be started without interruption
Is not intended to be used as birth control

28. Visanne Some of the symptoms of an allergic reaction may include:
shortness of breath, wheezing or difficulty in breathing, swelling of face,
lips, tongue or other parts of the body, rash, itching or hives on the skin
Do not take Visanne if have or have had a blood clot in:
blood vessels of the legs (DVT), lungs (PTE), heart (heart attack), brain
(stroke), other parts of the body.
Do not take Visanne if concerned about an increased risk of blood clot

29. Luteal Phase Support in In Vitro Fertilization
Progesterone supplementation of luteal phase of stimulated IVF cycles leads to higher pregnancy rates and is necessary for optimal results.
Progesterone can be administered orally, vaginally, or through I.M. injection
Oral dosing requires a higher concentration in order to compensate for first-pass liver metabolism. The bioavailability of the orally administered progesterone can be as low as 10%
Oral administration may result in noticeable sedative and anxiolytic effects due to progesterone metabolites that enhance inhibitory neurotransmission by binding to the GABAA receptor complex .

30. Progesterone supplementation
I.M injections of micronized progesterone in oil result in a higher peak and longer lasting plasma concentrations, a daily administration is required due to a rapid metabolism.
I.M injections are difficult to self-administer and are often painful. A common practice is to warm up the oil solution in order to decrease its viscosity in an attempt to reduce pain with injection.

31. Progesterone supplementation
Vaginally delivered progesterone to uterus leading to a higher progesterone concentration in endometrial tissue compared to blood serum
Vaginal progesterone supplementation is equally effective and better tolerated by patients than intramuscular preparations.
Sufficient evidence of efficacy and tolerability to make vaginal supplementation the main route of progesterone support in stimulated IVF cycles exists

32. Progesterone supplementation
There are no agreement on the standard dose of progesterone in luteal phase support.
Once-daily Crinone gel, or twice- or thrice-daily Endometrin, or micronized progesterone 200 mg thrice a day are optimal doses of vaginal progesterone for luteal phase support in IVF.
Patients should have a choice about which preparation to use based on convenience and cost considerations.

33. Timing of starting luteal support
In stimulated IVF/ICSI cycles, steroid production in first week after oocyte retrieval is likely to be well timed and more than sufficient, so the start of exogenous support is not apt to be critical within this window.
No difference between the three different times of start of luteal support (start luteal support at hCG day, at egg retrieval day and at day of embryo transfer)
Vaginal supplementation is best started within 24 to 48 hours after oocyte retrieval.

34. Progesterone supplementation
There is no need for serum progesterone level monitoring with vaginal supplementation as little correlation exists between serum levels and local endometrial effects or pregnancy outcomes.

35. Progesterone supplementation
First randomized study to conclude that prolongation of progesterone supplementation in early pregnancy has no influence on miscarriage rate, and thus no effect on delivery rate and progesterone supplementation can safely be withdrawn at time of a positive hCG test.
It is likely that continued progesterone support in early pregnancy beyond the first positive pregnancy test is of little value for successful outcome; however, there are insufficient data to date to establish the right time for discontinuing support.

36. hCG for luteal phase support
GnRH-antagonist cycles that are triggered with GnRH agonists and that involve fresh embryo transfers should have a modified luteal phase support regimen that includes small doses of hCG or LH preparations in addition to standard progesterone support for optimal outcomes.
one RCT where patients at ovum pick up were randomized to receive luteal support as either progesterone only or hCG only or combination of progesterone and hCG showed that there were no statistically significant differences with regard to main outcome parameter, clinical ongoing pregnancy rate
The odds ratio of OHSS was more than 3fold higher when hCG was added to luteal phase support regimen, confirming that progesterone alone is a better strategy

37. Estradiol for luteal phase support
Addition of oral estradiol to progesterone supplementation in the luteal phase of IVF cycles does not improve outcomes.

38. GnRH agonist for luteal phase support
Administration of 0.1 mg of GnRH agonist triptorelin on day 6 after ICSI led to a significant improvement of implantation and live birth rates after ICSI.
Increased ongoing pregnancy rate, increased luteal-phase serum hCG, estradiol and progesterone concentrations, possibly by a combination of effects on embryo and corpus luteum.
Conclusion: GnRH agonist addition during the luteal phase significantly increases the probability of live birth rates.

39. Thanks for your attention