Induction of ovulation

By Mohamed Elmahdy

Induction of ovulation Super ovulation

DOPPLER

when PI was > 3.0. the uterine Doppler flow indices have a high negative predictive value and sensitivity (in the ranges of 88 to 100% and 96 to 100% respectively)

Donald School Journal of Ultrasound in Obstetrics and Gynecology, April-June 2010

Hypothalamus

AP

GnRH

Hypothalamic-Pituitary-Gonadal Axis (HPG):

Females

LH surgeTonic LH

Progesterone

PGF2a

Estrogens

+

FSH

Estrogen

LH

FEMALE REPRODUCTIVE SYSTEM

HORMONAL REGULATION OF OOGENSIS AND OVULATION

OVULATION:

sharp surge in LH with simulataneous increase in FSH

Meiosis I resumes; oocyte and surrounding cumulus break away and are extruded

oocyte passes into oviduct

ECTOPIC IMPLANTATIONS

FSH window Period of time that is crucial for

selection of single dominant follicle from cyclically recruited cohort. After that the dominant follicle continue growing as its sensitivity to FSH is increased.

In stimulated cycles

Increase the length of FSH window that increase the number of selected follicles.

Anovulation

WHO classification• Group I: hypogonadotrophic

hypogonadism.• Group II: predominately polycystic ovary

syndrome.• Group III: ovarian failure.

WEIGHT REDUCTION

• Spontaneous pregnancy after weight reduction even less than 5 % of the body weight.

• Reduction of the CC or FSH dose

NICE 2013, SOGC

Clomiphene Citrate

• exhibits both estrogen agonist and antagonist properties, i.e. selective estrogen receptor modulating activity.

• Estrogenic agonist properties are manifest only when endogenous estrogen levels are extremely low.

Pharmacology • CC is a mixture, in approximately a 3:2 ratio, of 2

geometric isomers, enclomiphene and zuclomiphene

• Enclomiphene is the more potent isomer ,rises rapidly after administration and fall to undetectable concentrations soon thereafter.

• Half life : 5 days.• The inactive Isomer present in blood for 6- 8

weeks.

• During CC treatment, levels of both LH and FSH undergo a prolonged rise, compared with a natural cycle because of the prolonged ER depletion in the brain.

• FSH window is extended, leading to multiple follicle growth and a higher multiple pregnancy rate with CC than occurs in natural cycles.

Mechanism of action of CC

• CC binds to estrogen receptors (ERs) throughout the for an extended period of time, i.e.weeks rather than hours as with natural estrogen.

• Depletes ER concentrations by interfering with the normal process of ER replenishment.

• The antiestrogenic effect on the hypothalamus. estrogen concentrations are falsely perceived as low leading to increased GnRH production

• Actions at the pituitary level may also be involved.

x

Hypothalamus

AP

GnRH CC

LH surgeTonic LH

Progesterone

PGF2a

Estrogens

+

FSH

Estrogen

LH

x x

xx

X

• In ovulatory women, CC treatment increases GnRH pulse frequency .

• In anovulatory women with PCOS in whom the GnRH pulse frequency is already abnormally high, CC treatment increases pulse amplitude but not frequency

Contraindications

Negative progesterone challenge test

HCG• A meta-analysis of 7 studies comparing triggering

ovulation with hCG (1,461 patients) with urinary LH testing to identify the endogenous LH surge (1,162 patients) for timing IUI for women with unexplained infertility treated with CC reported:

That there were lower odds of pregnancy when an hCG trigger was used (139 of 1,461) compared with LH surge monitoring (138 of 1,162; odds ratio [OR] 0.74; 95% confidence interval [CI] 0.57–0.96) (80, 81).

Outcome of CC treatment

• induce ovulation in 60–80% of properly selected candidates.

• cycle fecundity is approximately 15% in women who ovulate in response to treatment, with higher chance of pregnancy in the first cycles .

• Amenorrheic women are more likely to conceive than oligomenorrheic women.

pregnancy is most likely to occur in the first 3 to 6 cycles, and therapy

beyond 6 cycles is generally not recommended.

Routine supplementation of the luteal phase with vaginal progesterone does

not seem to improve pregnancy rates in normo- ovulatory women stimulated

with clomiphene citrate for IUI.

Hum Reprod. 2010 Oct;25(10):2501-6

CC failure failure to conceive within six CC-induced

ovulatory cycles should be regarded as• clear indication to expand the diagnostic

evaluation to exclude other factors .• change the overall treatment strategy when

evaluation is already complete

Adverse effects

• 20% irritability and mood changes.• 10% vasomotor symptoms.• 6% abdominal discomfort.• 2% breast discomfort.• 2% nausea and vomiting.• 1% visual symptoms.• 1% headache.

Cervical mucus

Affect the quality or quantity of cervical mucus.

Endometrium • reduction in endometrial thickness in 30 % of

cases.• Reduction in glandular density and an

increase in the number of vacuolated cells.• Decreased uterine blood flow during the

early luteal phase and the peri implantation stage may also explain, at least in part, the poor outcome of CC treatment.

Follow up

(Good-practice points) used in the RCOG and NICE guidelines, recommend the use of US to monitor the ovaries during stimulation with CC. (NICE 2013)

J Obstet Gynaecol 2011 Oct;31(7):566-71.

1. Weight loss, exercise, and lifestyle modifications. (II-3A) (NICE 2013)

2. Clomiphene citrate has been proven effective in ovulation induction for women with PCOS and should be considered the first-line therapy. (I-A)

3. Metformin combined with clomiphene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone.(I-A)

4. Metformin may be added to clomiphene citrate in women with clomiphene resistance who are older and who have visceral obesity. (I-A)

5. Gonadotropin should be considered second-line therapy for fertility in anovulatory women with PCOS. The treatment requires ultrasound and laboratory monitoring. High costs and the risk of multiple pregnancy and ovarian hyperstimulation syndrome are drawbacks of the treatment. (II-2A)

6. For women who are taking clomifene citrate, do not continue treatment for longer than 6 months.

7. Do not offer oral ovarian stimulation agents (such as clomifene citrate, anastrozole or letrozole) to women with unexplained infertility

Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249.

• clomiphene plus dexamethasone treatment was effective (OR 9.46, 95% CI 5.1 to 17.7) compared to clomiphene alone.

• A significant improvement in the pregnancy rate was

reported for clomiphene plus combined oral contraceptives versus clomiphene alone.

No improvement in pregnancy rate if combined with

• Tamoxifen 20 mg • Dopamine agonists • Estradiol.

Tamoxifen

• Similar structure to clomiphene .• Studies showed no difference as regards

ovulation , pregnancy, abortion or adverse effects rates.

• 20- 40 mg daily for 5 days.

N acetyl cysteine

NAC as a safe and well-tolerated adjuvant to CC for induction of ovulation can improve the ovulation and pregnancy rates in PCOS patients. It may also have some beneficial impacts on endometrial thickness.

J Obstet Gynaecol Res. 2012 Sep;38(9):1182-6

Metformin Anovulatory women with polycystic ovary

syndrome who have not responded to clomifene citrate and who have a body mass index of more than 25 should be offered metformin combined with clomifene citrate because this increases ovulation and pregnancy rates. ( A )

Aromatase activity • conversion of androstenedione and

testosterone to estrone and estradiol, respectively.

• ovaries, brain, adipose tissue, muscle, liver, breast tissue, and malignant breast tumors.

• The main sources of circulating estrogens are the ovaries in premenopausal women and adipose tissue in postmenopausal women

Pharmacology • AIs are completely absorbed after oral

administration with mean terminal half-life of approximately 45 h with clearance mainly by the liver.

• Mild gastrointestinal disturbances account for most of the adverse events.

Indications for AIs in induction of ovulation.

• AI when used alone results in the development of one or two mature follicles and a significantly reduced risk for OHSS and multiple gestation.

• To achieve multiple ovulation, the addition of FSH to the AI is likely necessary. (augmet FSH response due to increase intrafollicular androgens)

CC (d 5).

Casper R F , and Mitwally M F M JCEM 2006;91:760-771

©2006 by Endocrine Society

On endometrium Decreasing E2 levels lead to up-regulation of

ERs in the endometrium, leading to rapid endometrial growth once estrogen secretion

is restored.

AIS Induction of ovulation after CC failure.

• failed ovulation induction or ovulation with a very thin midcycle endometrium (≤0.5 cm)

• 75% ovulation • 25% cumulative pregnancy rate after 3 cycles.

Optimal dose of AIs

• 5-d course of treatment is between 2.5 and 5.0 mg.

• Higher doses resulting in persistence of aromatase inhibition and estrogen levels too low for normal endometrial development by the time of ovulation.

• If combined with FSH give sequential not overlapping protocol.

Adverse effects

• Fewer than CC .• Hot flashes .

Pregnancy outcome

Less incidence of multiple pregnancy.Less miscarriage rate .

Congenital anomaly?????

In 2005, however, Health Canada and the manufacturing company of letrozole issued a “Physician Warning Letter” on the off-label use of letrozole for fertility and the possibility of embryotoxicity, fetotoxicity, and teratogenicity found in rats.

Health Canada Endorsed Important Safety Information on Femara (letrozole). Published November 17, 2005.

• Tulandi et al. retrospectively evaluated 911 newborns from letrozole and CC pregnancies. They found a 2.4% incidence of congenital malformations and chromosomal abnormalities in the letrozole group versus 4.8% in the CC group.

Fertil Steril 2006;85:1761–5.

Letrozole vs CCFrom the available data there is no convincing

evidence that letrozole is superior to clomiphene citrate and therefore the cost should be taken into account when using anti-oestrogens.

Cochrane 2011

GONADOTROPHINS

Fixed dose regimen In the fixed dose regimen, the gonadotropin

dose is kept constant throughout the stimulation. If the optimal staring dose has been determined, this protocol is simple to follow and results in good outcomes.

Step up• Start with 150 IU for 7 days • Increase by 75 IU if no response every 6 days• Till response occur continue till the criteria of

HCG

150 IU

225 IU

Day 36 days US 6 days or HCG

Low dose step up• start with one 75 IU of HMG from day 3 for 6

days. • The HMG dose was increased by half an

ampoule (37.5 IU) every 6 days until the leading follicle reached 10 mm in diameter.

• Thus the same dose (i.e. the threshold dose) was maintained until the criteria for triggering ovulanon (at least one follicle >18 mm in diameter) were achieved.

RB&E, 2014

Step down High starting dose of gonadotropins (300-450

IU) is used for the first 2 days, followed by a dose reduction (150-225 IU/day).

Urinary or recombinant • Whether or not urinary gonadotrophins

should be used as first choice compared with recombinant products is more a discussion

of purity, trace ability and costs. There is no convincing evidence of a significant difference in the probability of conception.

Cochrane 2011

Sequential CC Gonadotrophins

Sequential CC/gonadotropin therapy

• Standard CC treatment regimen, followed by low-dose (hMG) or (FSH) (75–150 IU/day for 3 days).

• Treatment is individualized thereafter in the same way as with traditional gonadotropin therapy, on the basis of transvaginal ultrasound examinations .

• The sequential CC/hMG regimen is as effective as hMG regimen for ovulation induction, produces satisfactory pregnancy results and reduces the treatment cost.

Arch Gynecol Obstet. 2013 Mar;287(3):591-7.

Cycle fecunditySimilar to that achieved by treatment

with gonadotropins alone .

Advantages • Reduction in the dose of Gonadotropin .• Reduction in the associated costs of

monitoring.• Clomiphene citrate–resistant anovulatory

women often are very sensitive to low doses of gonadotropins.

The number of oocytes retrieved being higher in letrozole group might indicate that letrozole might contribute to successful ovarian stimulation with a lower dosage of gonadotropins. Despite the lower peak estradiol levels, pregnancy rates being similar to other group also support the idea that letrozole can contribute to normal potential of implantation.

Glob J Health Sci. 2015 Sep 1;8(4):45762

Conclusions

7days

75 IU 150 IU

37.5-75 IU

7 days