Ovarian Stimulation

(Oral agents)CC failure

By Ahmad Saber

Pregnancy rate

Per cycle?Per patient?

How would you counsel couples?

Indication

• Male?• Unexplained?• Anovulation?

Technique

•With IUI•Without IUI

Treatment

•With hMG•Without hMG

Additional treatment

•With adjuvants•Without

Monitoring

•Ultrasound•Hormones•CM

Ovulation “follicular rupture”

•LH•hCG

Repetitive cycles

• Consecutive cycles “back to back”

•One cycle “washout” in between

When to start?

• Day 1, 2, 3• Day 5• After progestin withdrawal, or not?• Value of basal scan

For how long?

•3 days •5 days•10 days

Dose

•50•100•150•200

Should I give it to.…

• A patient who developed a cyst, or thin endometrium, or poor mucus in previous CC cycles

• A patient who had eye symptoms, epigastric pain, or to a patient who had it 5 times before !

Can I predict CC failure??

• Ultrasound• Hormones• BMI• Degree of hirsutism and acne• Did not do my homework!!– Male evaluation– Tubal factor– Uterine factor

Check the engine before you fly

What you know is better than what you do not know

Expensive is not always good

Ancient and historic could be more beautiful

The guiding principle for treatment of women with anovulatory infertility should

be restoration of the feedback system which selects a single follicle for ovulation … Treatment with gonadotropins should be restricted to women who are resistant

to clomiphene.

ESHRE Capri Workshop 2000

Objectives

1. Review pharmacology of clomiphene citrate2. Indications for use3. To define cloimphene failure, and next step

Action In normally cycling women, CC abolishes the negative feedback effect of estradiol on pituitary gonadotropin release.

Cc deliver a message to the hypothalamus that is the body lacking estrogen

FDA recommended the total dose does not exceed 750 mg.

N.B: Higher estrone concentrations found in obese women necessitate higher CC doses in order to compete with the endogenous estrogens for hypothalamic receptor sites.

pharmacokinetics• Cc is readily absorbed in the humans, is ecxreted

principally in the feces. • ˃50% of the dose is excreted within 5 days

• the remaining drug or metabolites are slowly excreted, for 6 weeks, from a sequestered enterohepatic recirculation pool.

The commonest indication for Cc induction of ovulation is

Type ΙΙ ovulatory dysfunction

Indications

• Infertility associated with luteal phase dysfunction

• Infertility associated with oligoovulation

• Artificial insemination

• Unexplained infertility requiring COH and IUI

• Unexplained infertility requiring COH for IVF.

The majority of the published data suggest an improvement in pregnancy rates in unexplained infertility with clomid therpy when compared to expectant management. Semin Reprod Endocrinol. 1996 Nov;14(4):339-44.

Meta-analysis demonstrated a higher cycle pregnancy rate (CPR) with CC and IUI

compared to timed intercourse in the natural cycle. Aust N Z J Obstet Gynaecol. 2004.

MonitoringMaryland “triple 7 regimen”o serum estradiol 7 days after the last clomiphene tablet, o serum progesterone 7 days later, and o pregnancy test after 7 more days

Ultrasound Very essential to diagnose LUF syndrome which can be missed with triple 7 regimen

US to confirm ovulation was performed on the day of IUI (day 0) and every day thereafter for

another 3 days (days 1, 2 and 3).

Ultrasound MonitoringOvulation is characterized both by a decrease in the size of a monitored ovarian follicle and by the appearance of fluid in the cul de sac .

It most often occurs when follicular size reaches about 21 to 23 mm, although it may occur with follicles as small as 17 mm or as large as 29 mm.

Because of the inconvenience and expense of serial measurements, routine use of ultrasound for documenting ovulation is discouraged. Instead, its use should be confined to the monitoring of ovulation induction or superovulation

Clinical Pearls1. Start with/without progestin induced bleeding, any day of

the cycle 2-52. 50% of pregnancies occur at the 50mg dose, additional

20% at the 100mg, so total 70% of pregnancies occur at the 100 mg dose for 5 days

3. The dose of cc that initiates ovulation should not be increased and should be maintained for 4-6 months

4. Most cc-initiated pregnancies occur within the first 3-6 ovulatory cycles.

5. For optimal results, the patient is advised to have intercourse every other day for 1 week beginning 5days after the last clomid tablet

6. In some cases luteal function needs to be monitored

Spontaneous LH surge VS

Exogenous hCG• It depends on :

Do IUIPrevious LUF syndrome

N.B.1: If the endometrial thickness is < 9 mm on preovulation TVS , administration of hCG should be delayed

N.B.2: Exogenous estrogen may suppress spontenous LH surge so if you use estrogen suplementation it is better to use hCG I.M

Timed intercourse may participate in clomiphene failure????

Intercourse every other day between

cycle days 10 and 18.

Cc and timed intercourse????

• Timing intercourse to coincide with ovulation causes stress and is not recommended.

Level C evidence

Stop Clomiphene

Clomiphene Failure

Ovulation failure Conception failure

Approximately 10–25% of anovulatory women will be unresponsive to maximal conventional doses of CC (200 mg or 250 mg per day for 5 days). Lobo et.al; Obst Gynec (1982) 60:497–501.

Ovulation failure “CC non responsivness”

ovulation failure despite maximal conventional doses, generally considered to be 250 mg for 5 days.

Increase duration of treatmentExtended CC course up to 10 days

Cut-off 150 mgs for 5 days???

conception failure

“inability to conceive in an apparent 4-6 month ovulatory Cc induction cycles ”

Luteal phase dysfunction is present in 50% of those patients

If not, rule out coexisting infertility factors

If not, rule out premature luteinizati on or LUF $ (biochemical ovulati on)

Although Cc is a magic drug for anovlatory patients

Poor responders to clomiphene: age >30 years, …….AMH amenorrhea, ………FSH elevated androgen levels Increase LH after clomiphene Obesity. Hum Reprod. 2005 Oct;20(10):2830-7.

Obesity and clomid

• Women who have a body mass index of more than 29 should be informed that they are likely to take longer to conceive. (B)

• Women who have a body mass index of more than 29 and who are not ovulating should be informed that losing weight is likely to increase their chance of conception. (B)

Do not start clomid therapy in anovulatory obese

woman except after weight reduction

Ovulation failure = Increase the dose of clomid = pregnancy failure

• If the patient ovulate on 50 or 100 mg clomid continue the ovulating dose before you increase the dose

• What do you think about early starting dose??

• After 3 ovulatory cycles if no pregnancy better to do IUI to bypass the cervix

Is it the only proble?m

1.inhibitory effects on the activities of C17-20-lyase and aromatase.

2. clomiphene exerts direct effects on ovarian steroidogenesis

Clomiphene inhibited decidual induction.

Clomiphene also inhibited implantation of blastocysts.

delayed histologic dating of the endometrium (38%) .

aberrant endometrial beta3 integrin

expression a failure in the down-regulation of PR

during the window of implantation Fertil Steril. 2005 Mar;83(3):587-93.

Increase dose or increase days on number of follicles

Increasing the dose of CC from 50 mg in the first cycle to 100 mg in the next cycle results in minimal increases in average number of small, medium and large follicles (≥ 12 mm from 2.4 to 2.6, ≥ 15 mm from 1.7 to 1.9, ≥ 18 mm from 1.2 to 1.3).

Extending the number of days that 50 mg of CC is taken to 8 or 10 days has been shown to result in ovulation in patients who did not respond to 200 or 250 mg CC for five days in a small series.

In order to increase the number of follicles or

rate of growth just add

Gonadotropins

Predict cc failure in PCOs

Some authors put prediction criteria for CC failure in PCOs cases

CC failure

Conception failure-Age-severity of the menstrual cycle Abnormality-other infertility factors

Ovulation failure-obesity -hyperandrogenism -insulin resistance

Loaded body +

loaded

ovary

=CC fa

ilure

Clinical management Clomiphene failure: 200mg

1. Ovulation failure• Total lack of response; approach:

DexamethasoneOthersIncreasing duration of cc therapy

• Partial lack of response; follicles, no ruptureCorrected by surrogate LH surge ?? Chorimon 10.000 I.U

2. Conception failure– Improve cervical mucous?? Estradiol 2 mg from 9th day to…..– Sequential E from day 12th day followed by P 3 days after LH

surge

LUF s

Silent problem

An extended 10-day course of clomiphene citrate (CC) in women with

CC-resistant ovulatory disorders.

RESULT(S):

ovulated (65%). (17%) conceived. Weight, body mass index, and hyperandrogenism did not predict responsiveness to the

extended duration CC. Side effects were similar to those reported during standard CC treatment.

CONCLUSION(S):

An extended 10-day course of CC provides a simple, noninvasive, and inexpensive alternative for a subset of women with ovulatory disorders that are refractory to standard CC treatment. Fertil Steril. 1996 Nov;66(5):761-4.

Dexamethasone

Indicated whenDHEA-S levels greater than 2.0 mcg/mL

Dexamethazone in the market called Dexazone 0.5 mg or Dexamethazone 0.5 mg

Dexa may reduce anti-E effect of Clomid on the endometrium

Regimens of Dexa

• Long continuous [samuel et al; 1990]

0.5 mg daily ( stopped if pregnancy occurs, check cortisol level 3 weeks after start of treatment if <2.0 mg/dL, reduce

the dose

• Long alternate days [Rittmaster et al; 1988]

• Short 0.5 mg/day days 5 to 9 [Daly et al,. Fertil Steril 1984]

2 mg/day days 3 to 12 [Parsanezhad et al; Fertil Steril 2002]

2 mg 5 to 14 [Elnashar et al,. Hum Reprod 2006]

Dexamethasone has 40 times the glucocorticoid effect of cortisol, therefore, daily doses greater than 0.5 mg every evening should be avoided to prevent the risk of adrenal suppression and severe side effects that resemble Cushing’s syndrome.

Dexa in clomiphene resistance0.5 mg dexa at night with CC

• CC resistance with high androgen, long dexa-Diamont and Evron 1981, 80% ovulated, 45% pregnancy-Lobo et al 1982, 60% ovulation

• CC resistance with normal androgen, long dexa-Singh et al 1992, 90% ovulation, 50% pregnancy

• Randomized double blind, non resistant patients, group A cc alone compared to group B CC+ dexa long, Daly et al 1984

-Group A 65% ovulation, 40% pregnancy-Group B 100% ovulation, 60% pregnancy

• CC resistance with high androgen, short dexa -Trott et al 1996, 80% ovulation, 35% pregnancy

• CC resistance with normal androgen, short dexa

Emperic

Emperic

Use of dexamethasone and Cc in the treatment of Cc resistant patients with polycystic ovary syndrome and normal DHEAS.

230 women with PCOS and normal DHEAS who failed to ovulate after a routine protocol of CC.

INTERVENTION(S): The treatment group received 200 mg of CC from day 5 to day 9 and 2 mg of DEX

from day 5 to day 14 of the menstrual cycle. The control group received the same protocol of CC combined with placebo. RESULT(S): 88% of the study group and 20% of the control group had evidence of ovulation.

The difference in the cumulative pregnancy rate in the treatment and control groups was statistically significant.

CONCLUSION(S): This regimen is recommended before any gonadotropin therapy or surgical

intervention. Fertil Steril. 2002.

Complications

• If 0.5 mg dexa, or 5 mg prednisone /day were used for less than 3 weeks, complications are rare, it can be stopped abruptly.

• The most common undesirable side effect is weight gain

Metformin

Metformin

• Nonsteroidal, water soluble, biguanide indirectly affecting ovarian function

• Unlike sulfonylureas it does not modify pancreatic insulin secretion

• Triple action:1. Inhibits hepatic gluconeogenesis2. Decreases intestinal absorption of glucose3. Increases glucose peripheral uptake and utilization4. No hypoglycemia

Clomid vs

Metformin

Six-month metformin administration is

significantly more effective than six-cycles CC

treatment in improving fertility in anovulatory PCOS

women, in terms of pregnancy, and abortion

rates. J Clin Endocrinol Metab. 2005 Jul

Clomid + Metformin

Cc resistant PCOS: metformin

• Metformin is as effective as LOD to improve “ovarian sensitivity” to subsequent 150 mg CC from day 3-7.

• The rate of ovulation in those who took metformin plus CC or CC alone was 76% versus 42%, respectively.

• Metformin may be effective by itself, it may take up to six months to appreciate ovulatory cycles .

Tonically elevated insulin

inapprpriate cell growth stimuli

abnormal folliculogenesis

PCOS

Tonically elevated insulin

apprpriate cell growth stimuli

Normal folliculogenesis

PCOS

Metformin

DangerousBut rare ..

Lactic acidosis1:33000

Myalgia Fatigue

Abdominaldistress

Respiratorydepression

500 500 500

500

500

500

1st week 2nd week 3rd week

Incremental dose protocol

Duration of treatment :

Long term ( up to one year )

BMI ˃30patient with glucose intoleranceAcanthosis nigricansHirsutism

Short term (up to 3 months )

BMI about 25-30Patient who already started induction

After 3 Cc induction cycles in which ovulation is confirmed 6-8 weeks of metformin pause before restarting

ovulation induction medications

Results • Monitoring • Ovulatory response• Conception

Continue or discontinue ???????• There has been some controversy as to whether

metformin decreases the chance of a first-trimester loss if taken throughout the early part of pregnancy.

• In a recent meta-analysis, it was concluded that metformin does not decrease the chance of a firsttrimester loss .

Clomid + metformin

VS

Clomid + OCs

COCs

Pretreatment with COCs the cycle before taking CC significantly increased ovulation rates and pregnancy rates in

a systematic review of randomized controlled studies .

Pretreatment with COCs is beneficial in PCOS patients, because they suppress serum and ovarian androgen levels

May be a cause of HyperPRL

COCs affect serum androgen by 3 mechanisms

Suppression of ovarian

androgensSHBG

productionSuppression of

Adrenal androgens

Unknown mechanismLH Free androgen

COC + Insulin resistance & secretion

• The available data demonstrate that insulin sensitivity may worsen during COC use in PCOS.

• However, the effect could be modified primarily by the degree of obesity.

• A decrease in insulin sensitivity is not a necessary consequence of COC use, especially in non-obese women where the influence may be neutral.

Adding Metformin to COC

• There are only two studies dealing with the combination of metformin + COC.

• There was no change in insulin sensitivity in either group.

• The only significant difference between both groups was a greater decrease in androgens after combined treatment.

Pretreatment with COC before clomid

In a study done to evaluate the effectiveness and endocrine response of COCs ovarian suppression followed by CC in patients who previously were CC resistant. (J Obstet Gynecol. 2003)

• 48 patients from a tertiary infertility clinic were assigned randomly prospectively to either:

• group 1 which received COCs followed by CC, • group 2 (control) received no treatment in the cycle

before CC treatment. • The COCs/CC group had significant: - higher percentage of ovulatory cycles. - higher pregnancy rate. - lower levels of E2, LH and androgens- that may be responsible for

the improved response- with no significant changes in group 2.

Suppression of the ovary with COCs results in excellent rates of ovulation and pregnancy in patients who previously were resistant to CC.

Dopaminergic agentsHow to suspect? Irregular cyclesGlactorrhea Severe Mastalgia as apart of PMS

How to confirm?Serum PRL at 10 o`clock in any day of follicular phase

By far the commonest cause of hyperPRL in females not took pills before is subclinical hypothyroidism so TSH must be ordered

How do we explain the woman who has normal menstrual cycles in the presence of hyperprolactinemia?

Dostinex Cabergoline 0.5 mg

Parlodel Bromocriptine 2.5 mg

Norprolac QUINAGOLIDE 75 μg

Dopergin Lusuride maleate 0.2 mg

Dostinex Cabergoline 0.5 mg

Parlodel Bromocriptine 2.5 mg

Norprolac QUINAGOLIDE 75 μg

Dopergin Lusuride maleate 0.2 mg

Tamoxifen

Tamoxifen

• Non steroidal compound with structural similarities to DES

• Structurally a triphenyl-ethylene derivative, an antiestrogen with weak estrogenic activity

• Chemically and functionally similar to clomiphene and can be used in hypothalamo-pituitary-ovarian dysfunction, patients should have adequate endogenous estrogen

Tamoxifenmechanism of action

• Competes for estrogen receptors on hypothalamus-pituitary

• Enhances folliculogenesis by a direct action on the ovary “”Gautam et al 1998””

• Same as clomiphene citrate in achieving ovulation

TamoxifenAdvantages ! Over clomiphene

• Higher pregnancy rates ?• Useful in some clomiphene resistant patients• PCOS with elevated LH• Women with poor cervical mucus• Better endometrium• Lower abortion rate• Better oocyte quality, developmental competence

Thyroxine???

Clomiphene-hMG

• Concurrent low-dose gonadotropin and oral drug protocol

CC 100 mg or TMX 60 mg are started on the same day as FSH or hMG and continued for five days.

FSH or hMG are continued until hCG is administered.

• overlap protocol

hMG and FSH are started one or two days later than the CC or TMX

This protocol requires estradiol levels > 50 pg/mL to start, and therefore cannot be used in GnRH-suppressed patients.

• Sequential protocol (oral drug followed by gonadotropin)

FSH or hMG is started on cycle day 8–10 after five days of oral CC or TMX.

The advantages of the sequential protocol are a lower medicine cost and in most cases the need for only a single US to monitor follicle development.

• CC 50–100 mg or TMX 20–60 mg are taken for five days.

• US should be normal and estradiol level ≥ 50 pg/mL.

• FSH or hMG 75 IU is started on day 8 or 10, after the last CC or TMX, and continued for three days.

• Day 11–13 US is performed and hCG is given if follicle and endometrial criteria are met.

• FSH or hMG may be given for 1–3 additional days until hCG criteria are met.

The disadvantages of the sequential protocol are that multiple pregnancy rates are as high as for the basic gonadotropin protocol. This protocol effectively rescues non-dominant follicles from atresia. It has no advantage over CC or TMX alone in patients who develop no more than one or two follicles with basic COH .

Comparative studies

• Several authors compared CC only with CC+hMG, and hMG only protocols

• Clomiphene only resulted in lower number of follicles (oocytes) as compared to the other two protocols

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Clomid 100

FSH 150

Clomid 100

FSH 150

Clomid 100

FSH 150

Clomid 100

FSH 150

Clomid 100

FSH 150

Diamond et al Fertil Steril 1986

Adeq

uate

resp

onse

E2 >

600

folli

cle>

14

2 days

hCG

Group 1

Group 2

Group 3

Group 4

Group 5 Higher fertilization

and pregnancy

rates

Prevent dominance

• In all protocols, follicles must start from the same line–Pills–Progestins–Agonist–Antagonist if you are late–FEMARA

“speed” of folliculogenesis

If too fast, oocytes are exhausted, and luteal

phase is deficient

p.o.: Abbreviation meaning by mouth, orally (from the Latin "per os", by mouth). One of a number of hallowed abbreviations of Latin terms that have traditionally been used in prescriptions.Some others:•a.c. = before meals (from "ante cibum", before meals)•b.i.d. = twice a day (from "bis in die", twice a day)•gtt. = drops (from "guttae", drops)•p.c. = after meals (from "post cibum", after meals)•p.r.n. = when necessary (from "pro re nata", for an occasion that has arisen, as circumstances require, as needed)•q.d. = once a day (from "quaque die", once a day)•q.i.d. = four times a day (from "quater in die", 4 times a day)•q._h.: If a medicine is to be taken every so-many hours (from "quaque", every and the "h" indicating the number of hours)•q.h. = every hour•q.2h. = every 2 hours•q.3h. = every 3 hours•q.4h. = every 4 hours•t.i.d. = three times a day (from "ter in die", 3 times a day)•ut dict. = as directed (from "ut dictum", as directed