COH

COHCOH

Dr. Vincenzo Volpicelli

Fertility Center Cardito

ClomipheneClomiphene

Seconda Università degli Studi di Napoli

SUNfert

Dipartimento di Scienze della Vita

Citrate ClomipheneCitrate Clomiphene

Greenblatt et al. in 1961Greenblatt et al. in 1961

remains the most commonly used drug in remains the most commonly used drug in the treatment of infertilitythe treatment of infertility

Clomiphene chemistryClomiphene chemistry

2-(4-(2-chloro-1,2-diphenylethenyl) phenoxy)-N,N-diethyl-ethanamine (CC2626HH2828CINO)CINO)

Clomiphene chemistryClomiphene chemistry

diastereomeric mixture of two geometric isomers:

EnclomifeneEnclomifene (E-clomifene)

and

ZuclomifeneZuclomifene (Z-clomifene)

CC pharmacokinetic dataCC pharmacokinetic data

o Bioavailability: high (>90%)o metabolism: hepatic (with

enterohepatic circulation)o half-life: 5-7 days **o excretion:

o mainly renal o some biliary fecal (oxide-CC,

4-OH-CC, defetyl-CC)

Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ: “single-dose Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ: “single-dose pharmacokinetics of clomiphene citrate in normal volunteers”. Fertil Steril 1986; 64:392-6 pharmacokinetics of clomiphene citrate in normal volunteers”. Fertil Steril 1986; 64:392-6

Enterohepatic circulationEnterohepatic circulation

Recycling through liver by excretion in Recycling through liver by excretion in bilebile

reabsorption from small intestine reabsorption from small intestine

into portal circulation into portal circulation back to the back to the liver. liver.

Enterohepatic CirculationEnterohepatic Circulation

porta veinporta vein

central veincentral vein

CC therapy requirementsCC therapy requirements

patient fallopian tubes

Women anovulatory MAP + (WHO group II) ** integrity of pituitary gland relatively normal (or elevated) gonadotropin levels evidence of significant endogenous estrogen

production

Unexplained infertility (?)

** World Health Organization Scientific Group Report . Consultation on the diagnosis and treatment of endocrine forms of female infertility. World Health Organization Technical Report Series 514. Geneva: World Health Organization; 1976

CC mode of actionCC mode of action

non-steroidal estrogen agonist/antag drugnon-steroidal estrogen agonist/antag drug

selective estrogen receptor modulator selective estrogen receptor modulator (SERM)(SERM)

pituitary glandpituitary gland hypothalamic neurons (ant & medio-basal)hypothalamic neurons (ant & medio-basal)

CC mode of actionCC mode of action

Estrogene receptor modulatorEstrogene receptor modulatorinhibits the negative feed-back of inhibits the negative feed-back of estrogensestrogens on the in the hypothalamic on the in the hypothalamic neurons and gonadotrope cells ofneurons and gonadotrope cells of anterior pituitary gland "Sensing" low anterior pituitary gland "Sensing" low estrogen levelsestrogen levels Gn-RH release is increasedGn-RH release is increasedFSH release is increased FSH release is increased

CC mode of actionCC mode of action**

Spontaneous Clomiphene

Follicular 21.6 +/- 2.9 23.8 +/- 3.1

Follicular rupture 15.1 +/- 1.85 16.1 +/- 2.9

This suggests that the follicle, under the influence of CC, has to reach a larger critical mass to produce enough estradiol to revert the hypothalamic blockage produced by the drug, thus permitting the preovulatory LH surge.

thickness 10.6 +/- 1.8 mm 11.1 +/- 2.02

** Huneeus A (Rev Chil Obstet Ginecol. 1994;59(6):463-8)

CC increasing fecundityCC increasing fecundity

increasing the number of oocytes increasing the number of oocytes overcoming subtle ovulatory disfunctionsovercoming subtle ovulatory disfunctions more precise timing of insemination more precise timing of insemination increasing the number of sperm in the increasing the number of sperm in the

upper female reproductive tractupper female reproductive tract

if forget a doseif forget a dose

Take the missed dose as soon as you remember it

Do not take a double dose to make up for a missed one

CC administrationCC administration

50-250 mg/d 50-250 mg/d

From 1°-6° cycle dayFrom 1°-6° cycle day

for 5-7 daysfor 5-7 days

Ovulation: 5-10 days after last pillOvulation: 5-10 days after last pill

Clomid, Serofene 50 mg tabletsClomid, Serofene 50 mg tablets

HCG 5.000 UI i.m. when leading follicle ≥18 mmHCG 5.000 UI i.m. when leading follicle ≥18 mmIUI 36 hours after HCG administrationIUI 36 hours after HCG administrationHCG 2.500 UI im 6 days after the first dose of HCGHCG 2.500 UI im 6 days after the first dose of HCG

CC administrationCC administration

HCG 5.000 UI i.m. when leading follicle ≥18 mm, if the LH HCG 5.000 UI i.m. when leading follicle ≥18 mm, if the LH surge was no detected surge was no detected

IUI 24-40 hours after HCG administration or spontaneous IUI 24-40 hours after HCG administration or spontaneous LH surgeLH surge

HCG 2.500 UI im 6 days after the first dose of HCGHCG 2.500 UI im 6 days after the first dose of HCG

Clomid or Serofene 50 mg tabletsClomid or Serofene 50 mg tablets

CC dose in obeseCC dose in obese

higher doseshigher doses**

CC is not stored in adipose tissueCC is not stored in adipose tissue

the need for an increased dose probably is due to:

a more intensive anovulatory state a more intensive anovulatory state

higher androgen levels higher androgen levels

*Gerli S, Fertil Steril. 2000 Jan;73(1):85-9

CC time of startCC time of start

day of initiation (1-2° or 5° cycle day)day of initiation (1-2° or 5° cycle day)

impact on the pregnancy rateimpact on the pregnancy rate

It is still controversialIt is still controversial

CC time of administeringCC time of administering

similar in both groups *Morphometric parameters,

histologic dating,

ultrasonographic appearance thickness of the endometrium

** Triwitayakorn A, et al (Fertil Steril. 2002 Jul;78(1):102-7)Triwitayakorn A, et al (Fertil Steril. 2002 Jul;78(1):102-7)


no differencesno differences** in oocyte quality:in oocyte quality:

the perifollicular vascularity the perifollicular vascularity

inin endometrial receptivity:endometrial receptivity:endometrial thickness endometrial thickness Doppler flow indices of ascending Doppler flow indices of ascending

branches of the uterine arteries branches of the uterine arteries and subendometrial vesselsand subendometrial vessels

*Cheung W, Ng EH, Ho PC: *Cheung W, Ng EH, Ho PC: Hum Reprod 2002 Nov;17(11):2881-4Hum Reprod 2002 Nov;17(11):2881-4

CC time of administeringCC time of administering**

**Biljan MM, Mahutte NG, Tulandi T, Tan SL (Fertil Steril. 1999 Apr; 71(4):633-8)Biljan MM, Mahutte NG, Tulandi T, Tan SL (Fertil Steril. 1999 Apr; 71(4):633-8)

1-5 days1-5 days 5-9 days5-9 days

FolliclesFollicles

numbernumber ++ + + ++ + +

++ + + ++ + +

follicular growth time follicular growth time + + ++ + + ++

CC-free period before IUICC-free period before IUI 8 (4-14) days8 (4-14) days 6 (2-7) days6 (2-7) days

Pregnancy rate/cyclePregnancy rate/cycle 25%25% 0%0%


**Dehbashi S, Vafaei H, Parsanezhad MD, Alborzi S (2006)Dehbashi S, Vafaei H, Parsanezhad MD, Alborzi S (2006)

1-5° days1-5° days 5-9° days5-9° days

ovulation ratesovulation rates 72.8%72.8% 70.8%70.8%

biologicalbiological

pregnancy ratespregnancy rates40.5%40.5% 19.5%19.5%

CC ovulation outcomeCC ovulation outcome

80% for cycle80% for cycle

Pregnancy OutcomePregnancy Outcome

USG pregnancy rate/cycle: 18% **

live-birth rates/cycle : 5-8% **

* * Published overallPublished overall

PO/Ovulation PO/Ovulation discrepancydiscrepancy

prolonged antiestrogenic effects on:prolonged antiestrogenic effects on:

endometrial receptivityendometrial receptivity * * cervical mucuscervical mucus ** **

uterine artery blood flowuterine artery blood flow

** Frydman R et al: (Fertil Steril. 1993;59:1179–1186) Frydman R et al: (Fertil Steril. 1993;59:1179–1186)

**** Gelety TJ, Buyalos RP. (Fertil Steril. 1993;60:471–476)

CC Adverse effects*CC Adverse effects*

uterine blood flow:uterine blood flow:

decreasesdecreases the the uterine blood flow uterine blood flow also during the also during the early luteal phase, a early luteal phase, a periimplantation periimplantation stagestage** 50

60

70

80

90

100

110

1° 5° 9° 14° 16° 19° 24°

**Hsu CC, Kuo HC, Wang ST, Huang KE. (Obstet Gynecol. 1995 Dec;86(6):917-21)

(Index Resistance)

Advantage CC vs. GnAdvantage CC vs. Gn

decreased risk of complications:

injection problems injection problems OHSS OHSS multiple birthsmultiple births


Hot flashes abdominal discomfort visual blurring weight gain reversible ovarian enlargement cyst formation increased risk of ovarian cancer fetal malformation

* ≥1% of patients* ≥1% of patients


spontaneous abortions (~30%) oocyte and embryo development endometrial morphology cervical mucus uterine blood flow

* ≥1% of patients* ≥1% of patients

CC increased abortion*


1.1. impaired endometrial development:impaired endometrial development:

• integrins (down regulation), markers of endometrial integrins (down regulation), markers of endometrial receptivityreceptivity

• endometrial estrogen and progesterone receptorsendometrial estrogen and progesterone receptors

• uterine artery flowuterine artery flow

attributed to several factorsattributed to several factors

CC increased abortion*


2.2. egg quality egg quality

3.3. cervical mucuscervical mucus

CC poor egg quality

CC-induced apoptosis in granulosa CC-induced apoptosis in granulosa cellscells

reducing E2 level in ovaryreducing E2 level in ovary

co-administered co-administered EE22

These adverse effects of CC were protectedThese adverse effects of CC were protected

Shail K. Chaube, Pramod V. Prasad M, Sonu C. Thakur and Tulsidas G. Shrivastav: “Estradiol protects clomiphene citrate–induced apoptosis in ovarian follicular cells and ovulated cumulus–oocyte complexes” Fertility and Sterility 2005; 84,2:1163-1172

CC + ECC + E22

CC 100 mg/d on 3° cycle day ethinyl E2 per os 0.05 mg daily on day 8 for 5-26 on day 8 for 5-26

daysdays hCG 10,000 IU at least one follicle was >18 mm A single IUI was performed 24–36 hours after the

administration of hCG progesterone 50 mg daily IM 3 days after IUI until β-

hCG levels were evaluated

Gerli. Intrauterine insemination. Fertil Steril 2000; 73,1:85-89Gerli. Intrauterine insemination. Fertil Steril 2000; 73,1:85-89

EE to reverse the antiestrogenic effects of CC*

CC only CC + EE

FSH, LH, E2 no s.s.d. no s.s.d

uterine a. PI no s.s.d no s.s.d

endometrial thickness + + + +

n. preovulatory follicles no s.s.d no s.s.d

pregnancy rate 6.25% 37.5%

miscarriage 18.75% 6.25%

EE22 0.05 mg daily co-admnistration 0.05 mg daily co-admnistration


EE to reverse the antiestrogenic effects of CC*


■ ■ = CC; □ = CC + ethinyl E2.= CC; □ = CC + ethinyl E2.

CC + IUI or ITCC + IUI or IT

IUI: A single IUI was performed 24–36 hours after the administration of hCG

Two IUI 24 and 48 h after

Intercourse timed

egg viability: 6-24 hegg viability: 6-24 hSperm viability: 48-72 hSperm viability: 48-72 h

0

10

20

30

40

%

unfriendlinesscervical

unexplainedsterility

male factors

CC + IUI Pregnancy OutcomeCC + IUI Pregnancy Outcome

Pregnancy rates lower : Pregnancy rates lower : **

over 38 years old low ovarian reserve poor quality sperm endometriosis any degree of tubal damage or pelvic scar

tissue couples with a long duration of infertility (over

about 3 years)

* * Infertility and IVF Specialist Clinic Gurnee & Crystal Lake, Illinois

luteal supplementationluteal supplementation

Starting 3 days after IUI, Starting 3 days after IUI, im injection of 50 mg of progesterone im injection of 50 mg of progesterone

daily (Prontogest; AMSA). daily (Prontogest; AMSA). ββ-hCG levels were evaluated.-hCG levels were evaluated.Laboratory determinations Laboratory determinations USG examinations 15-20 days after IUIUSG examinations 15-20 days after IUI

COH in CC-resistant

N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trial. [Acta Obstet Gynecol Scand. 2007]

A randomized controlled trial of the efficacy of rosiglitazone and clomiphene citrate versus metformin and clomiphene citrate in women with clomiphene citrate-resistant polycystic ovary syndrome. [Fertil Steril. 2006]

A prospective, double-blind, randomized, placebo-controlled clinical trial of bromocriptine in clomiphene-resistant patients with polycystic ovary syndrome and normal prolactin level. [Int J Fertil Womens Med. 2002]

Anastrozole or letrozole for ovulation induction in clomiphene-resistant women with polycystic ovarian syndrome: a prospective randomized trial. [Fertil Steril. 2008]

Use of dexamethasone and clomiphene citrate in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome and normal dehydroepiandrosterone sulfate levels: a prospective, double-blind, placebo-controlled trial. [Fertil Steril. 2002]

Multiple follicular recruitment and intrauterine insemination outcomes compared by age and diagnosis*

We studied the outcome of our intrauterine insemination (IUI) programme, evaluating female age and diagnosis. One-hundred-and-twenty-six patients <36 years of age (mean 30.91 ± 3.02 years) completed 306 cycles of multiple follicular recruitment (MFR) and timed IUI; 64 patients 36 years of age (mean 38.36 ± 2.08 years) completed 166 cycles (total 190 patients, 472 cycles). The male partners' semen was prepared for IUI with wash and swim-up techniques. Diagnostic groups were: male factor (n = 26), idiopathic (n = 33), endometriosis (n = 19), ovulatory disorder (n = 7), other (n = 19) and combined factors (n = 86). Pregnancy rates (% per couple, % per cycle) [overall (31.58, 12.7)] [<36 years (38.10, 15.69)] [>36 years (18.75, 7.23)] were greater in the <36 years group (P < 0.025). The probability of conception after three treatment cycles was 0.402 overall, 0.481 for age <36 years and 0.252 for age 36 years. The probability of conception for male factor and idiopathic infertility patients was 0.469 and 0.411 respectively. An age effect was found on pregnancy rates in the idiopathic group only. In conclusion, MFR + IUI is a valuable treatment especially for male factor patients and patients <36 years old, with idiopathic infertility

Horbay G.L.A: Human Reproduction, Vol. 6, No. 7, pp. 947-952, 1991Horbay G.L.A: Human Reproduction, Vol. 6, No. 7, pp. 947-952, 1991

THE END

Noyes criteria (1950)Noyes criteria (1950)

endometrial istologic changes during the menstrual cycle

Secretory glandes StromaEpitelium

Noyes RW, Hertig AT, Rock J: “Dating the endometrial biopsy”. Fertil Steril1950;1:3-9Noyes RW, Hertig AT, Rock J: “Dating the endometrial biopsy”. Fertil Steril1950;1:3-9

Insler cervical scoreInsler cervical score

PARAMETERS 0 1 2 3 SCORE

Mucus absent poor in drops plentiful . . .Spinbarkeit ** absent cm 2-3 cm 4-6 cm 8-10 . . .

Ferning absent linear incompletefully

developed dendrites

. . .

Cervix closed partly open open very open . . .total score . . .

0-3 inadequate follicular maturation0-3 inadequate follicular maturation10-12 optimal maturation10-12 optimal maturation

* * 10-13 mm10-13 mm before ovulationbefore ovulation

Insler cervical score Insler cervical score monitoring outcomemonitoring outcome

hCG injection following a mean of 2.5 days of hCG injection following a mean of 2.5 days of a cervical score of 9–12 a cervical score of 9–12

without the examiner's knowledge of estradiol without the examiner's knowledge of estradiol and ultrasound results.and ultrasound results.

•In 38% of the cases this decision coincided In 38% of the cases this decision coincided with that based on estradiol and ultrasound. with that based on estradiol and ultrasound. •In 57% of the cases there was a 1-day gap.In 57% of the cases there was a 1-day gap.

Oelsner G , S. B. Pan, S. P. Boyers, Tarlatzis B. C. and De Cherney A. H.: “The value of the cervical score in monitoring ovulation induction for in vitro fertilization: A prospective double-blind study”. Journal of Assisted Reproduction and Genetics; 1986; 3,6: 366-369.

Fern test (1955)Fern test (1955)

• cervical mucus smears form a fern pattern

• when estrogen secretion is elevated,

• as at the time of ovulation

• similar changes in saliva

Fern test (1955)Fern test (1955)

Berthou J and Chretien F.C.: “Double sodium and potassium sulphates revealed by microprobe Berthou J and Chretien F.C.: “Double sodium and potassium sulphates revealed by microprobe analysis in dried cervical mucus: a mid-cycle crystallographic index” (Human Reproduction analysis in dried cervical mucus: a mid-cycle crystallographic index” (Human Reproduction Update 1997;3,4: 347-358).Update 1997;3,4: 347-358).

•Clearly dependent on oestrogenic action

•Becomes increasingly marked as ovulation approaches

•Maximum ferning reflects maximum sperm receptivity•The core of the dendrites appears to be mainly composed of NaCl, but also of KCl.

Chrétien F.C. and Berthou J.: “Chrétien F.C. and Berthou J.: “A new crystallographic approach to fern-like A new crystallographic approach to fern-like microstructures in human ovulatory cervical mucus”. microstructures in human ovulatory cervical mucus”. Human Reproduction, Vol. 4, No. 4, Human Reproduction, Vol. 4, No. 4, pp. 359-368, 1989pp. 359-368, 1989

SpinbarkeitSpinbarkeit

Illustration depicting a health care worker Illustration depicting a health care worker testing the spinnbarkeit (stretchability, testing the spinnbarkeit (stretchability, elasticity) of the cervical mucous. elasticity) of the cervical mucous.

Spinbarkeit is the property of cervical Spinbarkeit is the property of cervical mucous to stretch a distance of 15 to 23 cm mucous to stretch a distance of 15 to 23 cm

MittelschmerzMittelschmerz

Mittelschmerz is one of the more common ovulation symptoms.

It is the name given to a pain in the pelvic area that is associated with ovulation.

The German word is derived from "mid-cycle pain".

It is a sharp pain lasting usually minutes or hours, typically not treated with pain relievers.

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