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Seconda Università degli Studi di Napoli
Dipartimento di Scienze della Vita
SUNfert
COH
Clomiphene
Fertility Center Cardito
Dr. Vincenzo Volpicelli
Citrate Clomiphene
Greenblatt et al. in 1961
remains the most commonly used drug in
the treatment of infertility
Clomiphene chemistry
2-(4-(2-chloro-1,2-diphenylethenyl) phenoxy)-N,N-diethyl-ethanamine
(C26H28CINO)
Clomiphene chemistry
diastereomeric mixture of two
geometric isomers:
Enclomifene (E-clomifene)
and
Zuclomifene (Z-clomifene)
CC pharmacokinetic data
o Bioavailability: high (>90%)
o metabolism: hepatic (with
enterohepatic circulation)
o half-life: 5-7 days *
o excretion:
o
o
mainly renal
some biliary  fecal (oxide-CC,
4-OH-CC, defetyl-CC)
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
Enterohepatic circulation
 Recycling through liver by excretion in
bile
 reabsorption from small intestine
 into portal circulation
liver.
back to the
Enterohepatic Circulation
central vein
porta vein
*
CC 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 action
 non-steroidal estrogen agonist/antag drug
 selective estrogen receptor modulator
(SERM)
 pituitary gland
 hypothalamic neurons (ant & medio-basal)
CC mode of action
Estrogene receptor modulator
inhibits the negative feed-back of
estrogens on the in the hypothalamic
neurons and gonadotrope cells of
anterior pituitary gland "Sensing" low
estrogen levels
Gn-RH release is increased
FSH release is increased
CC 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 fecundity
 increasing the number of oocytes
 overcoming subtle ovulatory disfunctions
 more precise timing of insemination
 increasing the number of sperm in the
upper female reproductive tract
if 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 administration
50-250 mg/d
From 1°-6° cycle day
for 5-7 days
Ovulation: 5-10 days after last pill
HCG 5.000 UI i.m. when leading follicle ≥18 mm
IUI 36 hours after HCG administration
HCG 2.500 UI im 6 days after the first dose of HCG
Clomid, Serofene 50 mg tablets
CC administration
HCG 5.000 UI i.m. when leading follicle ≥18 mm, if the LH
surge was no detected
IUI 24-40 hours after HCG administration or spontaneous
LH surge
HCG 2.500 UI im 6 days after the first dose of HCG
Clomid or Serofene 50 mg tablets
CC dose in obese
higher doses*
CC is not stored in adipose tissue
the need for an increased dose
probably is due to:
a more intensive anovulatory state
higher androgen levels
*Gerli S, Fertil Steril. 2000 Jan;73(1):85-9
CC time of start
day of initiation (1-2° or 5° cycle day)
impact on the pregnancy rate
It is still controversial
CC 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)
CC time of administering
no differences*
in oocyte quality:
the perifollicular vascularity
in endometrial receptivity:
endometrial
thickness
Doppler flow indices of ascending
branches of the uterine arteries
and subendometrial vessels
*Cheung W, Ng EH, Ho PC: Hum Reprod 2002 Nov;17(11):2881-4
CC time of administering*
1-5 days
5-9 days
Follicles
number
+
+++

+
+++
follicular growth time
+++
+
CC-free period before IUI
Pregnancy rate/cycle
8 (4-14) days 6 (2-7) days
25%
0%
*Biljan MM, Mahutte NG, Tulandi T, Tan SL (Fertil Steril. 1999 Apr; 71(4):633-8)
CC time of administering
1-5° days
5-9° days
ovulation rates
72.8%
70.8%
biological
pregnancy rates
40.5%
19.5%
*Dehbashi S, Vafaei H, Parsanezhad MD, Alborzi S (2006)
CC ovulation outcome
80% for cycle
Pregnancy Outcome
USG pregnancy rate/cycle: 18% *
live-birth rates/cycle : 5-8% *
* Published overall
PO/Ovulation discrepancy
 prolonged antiestrogenic effects on:
endometrial receptivity *
 cervical mucus **
 uterine artery blood flow

*
Frydman R et al: (Fertil Steril. 1993;59:1179–1186)
** Gelety TJ, Buyalos RP. (Fertil Steril. 1993;60:471–476)
CC Adverse effects*
uterine blood flow:
decreases the
uterine blood flow
also during the
early luteal phase, a
periimplantation
stage*
(Index Resistance)
110
100
90
80
70
60
50
1°
5°
9°
14°
16°
19°
24°
*Hsu CC, Kuo HC, Wang ST, Huang KE. (Obstet Gynecol. 1995 Dec;86(6):917-21)
Advantage CC vs. Gn
decreased risk of complications:
injection problems
 OHSS
 multiple
births

CC Adverse effects*
 Hot flashes
 abdominal discomfort
 visual blurring
 weight gain
 reversible ovarian enlargement
 cyst formation
 increased risk of ovarian cancer
 fetal malformation
* ≥1% of patients
CC Adverse effects*
 spontaneous abortions (~30%)
 oocyte and embryo development
 endometrial morphology
 cervical mucus
 uterine blood flow
* ≥1% of patients
CC increased abortion*
attributed to several factors
1. impaired endometrial development:
•
integrins (down regulation), markers of endometrial
receptivity
•
endometrial estrogen and progesterone receptors
•
uterine artery flow
*Gerli S, Fertil Steril. 2000 Jan;73(1):85-9
CC increased abortion*
2. egg quality
3. cervical mucus
*Gerli S, Fertil Steril. 2000 Jan;73(1):85-9
CC poor egg quality
CC-induced apoptosis in granulosa
cells
reducing E2 level in ovary
co-administered E2
 These 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 + E2
 CC 100 mg/d on 3° cycle day
 ethinyl E2 per os 0.05 mg daily on day 8 for 5-26
days
 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 βhCG levels were evaluated
Gerli. Intrauterine insemination. Fertil Steril 2000; 73,1:85-89
EE to reverse the
antiestrogenic effects of CC*
E2 0.05 mg daily co-admnistration
FSH, LH, E2
uterine a. PI
endometrial thickness
CC only
no s.s.d.
no s.s.d
+
CC + EE
no s.s.d
no s.s.d
+++
n. preovulatory follicles
pregnancy rate
miscarriage
no s.s.d
6.25%
18.75%
no s.s.d
37.5%
6.25%
*Gerli S, Fertil Steril. 2000 Jan;73(1):85-9
EE to reverse the
antiestrogenic effects of CC*
■ = CC; □ = CC + ethinyl E2.
*Gerli S, Fertil Steril. 2000 Jan;73(1):85-9
CC + 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 h
Sperm viability: 48-72 h
CC + IUI Pregnancy Outcome
%
40
30
20
10
0
unfriendliness
cervical
unexplained
sterility
male factors
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 supplementation
 Starting 3 days after IUI,
 im injection of 50 mg of progesterone
daily (Prontogest; AMSA).
 β-hCG levels were evaluated.
 Laboratory determinations
 USG 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-andtwenty-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, 1991
THE END
Noyes criteria (1950)
endometrial
istologic
changes
during the menstrual cycle
Secretory glandes
Stroma
Epitelium
Noyes RW, Hertig AT, Rock J: “Dating the endometrial biopsy”. Fertil Steril1950;1:3-9
Insler cervical score
PARAMETERS
0
1
2
3
Mucus
absent
poor
in drops
plentiful
Spinbarkeit *
absent
cm 2-3
cm 4-6
cm 8-10
Ferning
absent
linear
incomplete
fully
developed
dendrites
Cervix
closed
partly open
open
very open
total score
0-3 inadequate follicular maturation
10-12 optimal maturation
SCORE
...
...
...
...
...
Insler cervical score
monitoring outcome
 hCG injection following a mean of 2.5 days of
a cervical score of 9–12
 without the examiner's knowledge of estradiol
and ultrasound results.
•In 38% of the cases this decision coincided
with that based on estradiol and ultrasound.
•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
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)
•Becomes increasingly marked as ovulation approaches
•Clearly dependent on oestrogenic action
•Maximum ferning reflects maximum sperm receptivity
•The core of the dendrites appears to be mainly
composed of NaCl, but also of KCl.
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 Update 1997;3,4: 347-358).
Chrétien F.C. and Berthou J.: “A new crystallographic approach to fern-like
microstructures in human ovulatory cervical mucus”. Human Reproduction, Vol. 4, No. 4,
pp. 359-368, 1989
Spinbarkeit
Illustration depicting a health care worker
testing the spinnbarkeit (stretchability,
elasticity) of the cervical mucous.
Spinbarkeit is the property of cervical
mucous to stretch a distance of 15 to 23 cm
Mittelschmerz
 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.