? Controlled ovarian hyperstimulation:

clomiphene citrate, with the objective of multifollicular recruitment and hence

retrieval of multiple oocytes.

cannulation of the fallopian tubes

ovaries and fertilized extracorporeally with subsequent embryo replacement.

In vitro fertilization after retrieval of preovulatory oocyte(s) from

unstimulated ovaries.

Harvest of oocytes from the ovaries, either with laparoscopic- or

ultrasound-guided follicular aspiration.

Biologic age or an individual’s oocyte. Diminished ovarian reserve, which may be

? Tubal Factor Infertility

‚ Endometriosis

ƒ Male Factor Infertility

­ PS.:

… Immunologic Infertility

† In Utero Diethylstilbestrol Exposure

w The age of the female partner is the major determinant of IVF outcome

w Women older than 40 years have a markedly diminished prognosis compared with their

younger counterparts.

w The reduced chance for a viable pregnancy with increasing age results not only from

diminished implantation rates but also from an increased miscarriage rate of

approximately 60 %.

w It is the aging of the oocytes (ie. The decrement in ovarian reserve) rather than uterine

senescence that leads to age-related decline in success after IVF.

w A reflection of the biologic age of the follicle-oocyte complex

cycle day 3)

w An elevated day 3 FSH value (> 15 to 20 mIU/mL) may be secondary to a diminished

ovarian capacity to secrete inhibin and/or other factors and is indicative of incipient

ovarian failure and a substantially reduced probability of success after IVF.

w Ultimately, women displaying evidence of significantly diminished ovarian reserve

should be considered potential candidates for donor oocyte.

w In cases of severe male factor infertility, options including oocyte micromanipulation

ü Clomiphene Citrate:

- Infrequently employed as a single agent for IVF

- Disadvantages:

j High cancellation rate (25-40%)

¶ Poor response

¶ Premature LH surge

¶ Harvest of small numbers of oocytes (typically 1 or 2 per cycle)

k High frequency of endogenous LH surges (¶ spontaneous ovulation)

ž Oocyte retrievals at any hour of the day or night

v Clinical Usage:

? Concurrent:

† CC 50-150 mg po qd since D_4/5

† HMG (and/or FSH) 75-150 IU im. qd since D_4/5

† Cycle monitoring (serial sonographic follicular measurement and E₂)

† hCG 5000-10000 IU im.

When the lead follicles attain a mean diameter of at least 18 mm

† Oocyte retrieval 34-36 hours post hCG injection

‚ Sequential:

† CC 50-150 mg po qd D_4/5-D_8/9

† HMG (and/or FSH) 75-150 IU im. qd since D_9/10

† Cycle monitoring (serial sonographic follicular measurement and E₂)

† hCG 5000-10000 IU im.

When the lead follicles attain a mean diameter of at least 18 mm

† Oocyte retrieval 34-36 hours post hCG injection

v Drawback: spontaneous ovulation, which leads to a nighttime retrieval or cycle cancelation

v Clinical Usage:

When employed for IVF, gonadotropin administration is usually initiated on the

second or third day of the cycle at a dose ranging from two to four ampules in an effort to

maximize the recruitment of follicles from the gonadotropin-sensitive pool. The cycle is

monitored with daily estradiol determinations commencing after 2 to 3 days of therapy;

serial sonographic follicular studies are performed once the estradiol concentration exceeds

a threshold level, typically by the sixth or seventh day of the cycle. Approximate timing of

the ovulatory dose of hCG is important and is determined by a number of parameters,

including the mean diameter of the lead follicles (typically larger than 15 mm), the absolute

estradiol level (eg. > 400 to 500 pg/mL), and the patterns of follicular growth and estradiol

rise. Premature hCG injection may lead to the recovery of predominantly immature oocytes;

if injection is delayed, the oocytes may be postmature. Oocyte retrieval is performed

between 34 and 36 hours after the administration of hCG. Intensive LH monitoring is

unnecessary because the incidence of endogenous LH surges during gonadotropin only

stimulation is low (< 10%)

v Tapering Regimen (Step-down Protocol):

HMG and pure FSH can be given individually or in combination. The daily dose of

gonadotropins may be fixed or progressively increased or tapered according to the given

patient’s response. In the tapering regimen, the highest dose of HMG and/or FSH (four to

six ampules) is given on cycle day 3 and 4 and is then gradually reduced to two ampules

daily once follicular recruitment has been achieved.

¶ High responder: mean peak E₂ > 2000 pg/mL (ongoing pregnancy rate 41% per cycle)

¶ Intermediate responder:

¶ Low responder: mean peak E₂ < 400 pg/mL (success rate 19.6%)

v Criteria for Cycle Cancelation:

? Lack of response: E₂ < 100 pg/mL after 5 days of stimulation

‚ A falling E₂ level on 2 consecutive days of treatment

ƒ A 20% to 30% drop in the E₂ concentration on the morning after hCG administration

„ Recruitment of a single dominant follicle

- Specifically indicated for induction of ovulation in patients with hypothalamic amenorrhea

v Mechanism of Action:

ë Enhanced binding affinity to the GnRH receptor and to decreased susceptibility to

degradation by endopeptidases

’ Net effects: prolonging the half-life and augmenting the biologic activity of these

compounds

　

ë Initial Effect:

A surge of gonadotropin release from the ant. pituitary

ë Effect of Prolonged GnRH Receptor Occupancy:

Desensitization and downregulation of gonadotropins, eventuating in reversible

hypogonadism

v Clinical Usage:

? Long GnRH Analog Protocol:

- Administered since midluteal phase of the preceding cycle (D- ₇) until injection of hCG

- Principal disadvantage:

Increased dosage requirement for and duration of treatment with gonadotropins

ð Increased in both cost and the total number of injection

‚ Short GnRH Analog Protocol (Flare-up GnGH Analog Protocol):

- Administered since early follicular phase (D_2/3) until injection of hCG

v Advantages:

? Allowing a more even distribution of an IVF program

‚ Leading to an overall improvement in IVF success rates

v Disadvantages:

- Increased cost due to an increased gonadotropin dose requirement

- Increased duration of therapy

- Potential oversuppression of women with diminished ovarian reserve (ie. D₃ FSHJ )

- Possible increased risks of OHSS in high responders

- Formation of ovarian cysts

- OHSS as a direct result of the GnRH agonist alone

- Untoward effects on early embryogenesis

è Low Responders: (mean peak E₂ < 400 pg/mL)

- Often, a low response to stimulation may be attributed to diminished ovarian reserve

(advanced biologic ovarian age), but in other instances indices of ovarian function (ie.

D₃ FSH and E₂) are normal, and the poor response is unexplained.

- Strategy in the management of low responders:

j 50% reduction in the standard dose of GnRH analog

- Strategy in the management of high responders:

Ÿ Reduce dosage of gonadotropins

Principles: Adjust dosage individualizedly to meet the optimal condition

on which at least 3 follicles in size of 1.8 mm or more on D_12±

? Intermediate Responders:

Lupron: 0.2 cc/day since D_-7 to D₂

1. cc/day since D₃ to the day of hCG injection

HMG: 2 ampules/day since D₃ to the previous day of hCG injection

FSH: 2 ampules/day since D₃ to the previous day of hCG injection

‚ Strategy for Possible Poor Responders:

(eg. > 40 y/o, FSH > 15/or E₂ > 80, FSH > 13 and E₂ > 45, IUI failure for twice, etc.)

Lupron (half dose): 0.1 cc/day since D_-7 to D₂

  2 weeks post oocyte retrieval

  Exogenous hCG from the preretrieval injection is generally cleared within 9 days.

  In a successful IVF cycle, pregnancy is first documented by a positive hCG titer 12

to 14 days after oocyte retrieval.

l TVS

- Superovulation may lead to a suboptimal, nonphysiologic endocrine milieu.

- Exogenous progesterone support:

Initiating on the day after oocyte recovery, im., vt, or po.

j Pregnancy loss (20%):

- Most as first trimester spontaneous abortion

- 50% in women older than 40 y/o

- Factors:

1. Adverse endometrial impact of supraphysiologic ratios of E₂/P
2. Increased incidence of genetically abnormal oocytes and embryos after superovulation.
3. Close surveillance of an inherently higher-risk population

1. Reproductive Endocrinology, Surgery, and Technology; Adashi, Rock, and Rosenwaks; 1996.

Filename: IVF