13. 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 !
14. Can I predict CC failure ??
• Ultrasound
• Hormones
• BMI
• Degree of hirsutism and acne
• Did not do my homework!!
– Male evaluation
– Tubal factor
– Uterine factor
19. 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
21. 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.
22. 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.
24. 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.
25. 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.
26. 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.
27. Monitoring
Maryland “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).
28. Ultrasound Monitoring
Ovulation 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
29. Clinical Pearls
1. Start with/without progestin induced bleeding,
any day of the cycle 2-5
2. 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
30. Spontaneous LH surge
VS
Exogenous hCG
• It depends on :
Do IUI
Previous 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
31. Timed intercourse may participate in
clomiphene failure????
Intercourse every
other day between
cycle days 10 and 18.
32. Cc and timed intercourse????
• Timing intercourse to coincide with ovulation
causes stress and is not recommended.
Level C evidence
36. 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.
37. Ovulation failure “CC non responsivness”
ovulation failure despite maximal conventional doses,
generally considered to be 250 mg for 5 days.
Increase duration of treatment
Extended CC course up to 10 days
Cut-off 150 mgs for 5 days ???
39. 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.
40.
41. 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)
42. 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 problem?
43. 1.inhibitory effects on the activities of C17-20-lyase
and aromatase.
2. clomiphene exerts direct effects on ovarian
steroidogenesis
44. 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.
45. 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
46.
47. 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
48.
49.
50. Clinical management Clomiphene failure:
200mg
1. Ovulation failure
• Total lack of response; approach:
Dexamethasone
Others
Increasing duration of cc therapy
• Partial lack of response; follicles, no rupture
Corrected 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
51. 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.
52.
53. Indicated when
DHEA-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
54. 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]
55. 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.
56. Dexa in clomiphene resistance
0.5 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
57. 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.
58. 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
59.
60. Metformin
• Nonsteroidal, water soluble, biguanide indirectly
affecting ovarian function
• Unlike sulfonylureas it does not modify pancreatic
insulin secretion
• Triple action:
1. Inhibits hepatic gluconeogenesis
2. Decreases intestinal absorption of glucose
3. Increases glucose peripheral uptake and utilization
4. No hypoglycemia
63. 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
65. 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 .
70. Duration of treatment :
Long term ( up to one year )
BMI ˃30
patient with glucose intolerance
Acanthosis nigricans
Hirsutism
Short term (up to 3 months )
BMI about 25-30
Patient who already started induction
71. After 3 Cc induction cycles in which
ovulation is confirmed 6-8 weeks of
metformin pause before restarting
ovulation induction medications
72. 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 .
75. 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
76. ect serum androgen by 3 mechanisms
Suppression of
ovarian
androgens
SHBG
production
Suppression of
Adrenal androgens
Unknown
mechanismLH Free androgen
77. 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.
78. 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.
79. 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.
80. Suppression of the ovary with COCs results in
excellent rates of ovulation and pregnancy in
patients who previously were resistant to CC.
81. How to suspect?
Irregular cycles
Glactorrhea
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
82. How do we explain the woman who has normal menstrual cycles in
the presence of hyperprolactinemia?
86. 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
87. Tamoxifen
mechanism 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
88. Tamoxifen
Advantages ! 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
89.
90.
91. • 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.
92. • 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.
93. • 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 .
94. 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
95. 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
Adequateresponse
E2>600
follicle>14
2 days
hCG
Group 1
Group 2
Group 3
Group 4
Group 5 Higher
fertilization
and
pregnancy
rates
96. Prevent dominance
• In all protocols, follicles must start from
the same line
–Pills
–Progestins
–Agonist
–Antagonist if you are late
–FEMARA
98. 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
