Reproductive BioMedicine Online 20 Suppl.
3 (2010) S44–S45
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Ovulation Induction
106
AROMATASE INHIBITOR FOR OVULATION INDUCTION
M. Abou Abdallah. Middle East Fertility Center, Egypt
Aromatase is a member of the cytochrome P450 hemoprotein
containing enzyme complex super family. It catalyzes the rate-
limiting final step in estrogen (E) production, the hydroxylation
of androstenedione to estrone and of T to E2. Its activity can
be demonstrated in the ovaries, adipose tissue, placenta, brain,
muscle, fibroblasts, osteoblasts, liver, and breast.
For many years, aromatase inhibitors have been used as an
adjunct treatment for breast cancer. They could be steroidal
or nonsteroidal inhibitors. Steroidal inhibitors are derivatives of
androstenedione that act as false substrates, binding irreversibly
to the androgen-binding site.
The third-generation aromatase inhibitors include two nons-
teroidal inhibitors, anastrozole and letrozole, and a steroidal
agent, exemestane. Anastrozole and letrozole are selective
aromatase inhibitors. They are reversible and highly potent.
Letrozole and anastrazole are completely absorbed after oral
administration, with a mean half-life of approximately 45 hours
(range, 30 60 hours).
Estrogen exerts a negative feedback on the hypothalamic-
pituitary axis and decreases the release of FSH from the pituitary
gland. Blocking E production by inhibiting aromatization, would
release the hypothalamic-pituitary axis from estrogenic negative
feedback. As a result, FSH secretion increases, stimulating the
development of ovarian follicles. Because aromatase inhibitors
block high levels of E from androgen conversion, the effects
in women with polycystic ovary syndrome (PCOS) are more
prominent. In addition, androgens that normally converted to
estrogens accumulate in the ovary, and these androgens increase
follicular sensitivity to FSH. Unlike CC, aromatase inhibitor
does not deplete E receptors or produce a negative effect on
the endometrium. Clomiphene citrate, on the other hand, has
a longer half-life (2 weeks) that results in prolonged central
E receptor depletion.
Aromatase inhibitors are a new group of drugs to join the
arsenal of fertility treatments. They are orally administered,
easy to use, and relatively inexpensive, with minor side effects.
Anastrazole and letrozole are third-generation aromatase
inhibitors that have been used for ovulatory disorders and for
superovulation.
The data on letrozole suggest that it can be used to replace
CC as the first-line treatment for women with ovulatory
disorders. Compared with CC, its use is associated with thicker
endometrium. For superovulation, there is a trend for higher
pregnancy rates with letrozole than with CC. When letrozole is
added to gonadotropin regimens, it leads to less gonadotropin
requirement and a pregnancy rate that is comparable to that
with gonadotropin-only treatment.
It seems that the dose of 5 mg daily for 5 days is the most
effective.
1472-6483/$ - see front matter © 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
Aromatase inhibitors are promising new drugs for the induction of
ovulation and superovulation. After 4 decades of CC treatment,
a new era of ovulation induction has finally arrived.
107
CHOICE OF OVULATION INDUCTION PROTOCOL IN IVF
PATIENTS WITH ADENOMYOSIS
M.A. Gubanova, I.N. Lukoshkina, A.V. Semenov, A.M. Karpenko.
Embryo Clinic, Krasnodar, Russia
Aim:
Comparing effectiveness of ultralong ovulation induction proto-
cols with intranasal Busereline and Gosereline Depot in IVF for
adenomyosis patients.
Materials and Methods:
The study included 70 patients (mean age 32.8±5.1 years)
with history of unsuccessful IVF attempts. Forty-four (62.9%)
women had tubal infertility, 26 (37.1%) stages I II of
endometriosis (with no fertility restoration after surgery and
hormone therapy). Mean duration of infertility period was
5.8±2.1 years. All patients were diagnosed with adenomyosis
during the hysteroscopy which took place on Days 5 7 of the
menstrual cycle.
The patients were divided into two groups. Group 1 comprised
36 IVF patients who used 0.2% Busereline acetate solution as
a nasal spray in dose 900 mg daily starting from Day 2 of the
menstrual cycle. Ovulation induction was started on Day 45 of
Busereline use; the latter continued until the day of ovulation
trigger administration. Group 2 consisted of 34 patients who used
Gosereline Depot 3.6 mg (two s. c. injections, interval 28 days).
Ovulation induction was initiated on Day 12 after the second
injection. In both groups, recombinant human FSH (rhFSH) was
used for controlled ovarian hyperstimulation. Oocyte retrieval,
fertilization and embryo cultivation were standard. Two good-
quality embryos were replaced in the uterus on Days 3 5 post-
oocyte retrieval.
Results:
The comparison of two protocols has shown that the duration
of gonadotrophimn therapy was longer when using Gosereline
Depot (mean duration 11 days); for Busereline, it reached
9 days. Starting dose of rhFSH was higher in Group 2 (250
300 IU/d) compared with Group 1 (150 200 IU/d). Total rhFSH
dose in Group 1 patients was between 1050 and 1850 IU (mean
dose 1600 IU), which was less than in Group 2 (2050 2500 IU,
mean 2300 IU). There were no statistically significant differences
between the groups in terms of folliculogenesis, oogenesis and
early embryogenesis. Sixteen (44.5%) Group 1 patients and 13
(38.2%) Group 2 patients became pregnant.
Conclusion:
Intranasal Busereline use in ultralong protocol in adenomyosis IVF
patients leads to less pronounced suppression of hypothalamic-
pituitary-ovarian axis in the desensitization period compared
with Gosereline Depot use. It allows for adequate folliculogenesis
Ovulation Induction
in response to subsequent gonadotrophic stimulation and
decrease the total dose of gonadotrophins owing to reduction
of ovulation induction duration and lower starting doses of
gonadotrophins.
108
FIRST-LINE TREATMENT OF ANOVULATORY PCOS
R. Homburg. Barzili Medical Center, Ashkelon, Israel and
Homerton University Hospital, London, UK
Clomiphene citrate (CC), has been the medication of choice
for the first-line treatment for anovulatory PCOS for 50 years.
It induces ovulation in about 75%, pregnancy in 35%, 20%
miscarriages and 8 10% multiple pregnancies, so that 25% of CC
starters will have a singleton live birth. Ultrasound monitored
CC-treated cycles produce better pregnancy rates compared
with non-monitored cycles. The discrepancy between ovulation
and pregnancy rates is mostly explained by the anti-estrogen
effects of CC on endometrium. A serious alternative to CC
is letrozole, an aromatase inhibitor which causes a sharp
discharge of endogenous FSH by inducing an efficient block of
estrogen production, does not affect estrogen receptors in the
endometrium or hypothalamus and has a shorter half-life than
CC. These theoretical advantages over CC have been borne out
by reports of superior pregnancy rates induced by letrozole. Early
suspicion of possible teratogenic effects of letrozole have not
been substantiated.
As a result of several well-conducted trials, the use of insulin-
sensitisers such as metformin is not recommended for first-
line treatment in preference to CC although it may be useful
additively in CC-resistance.
Failure to ovulate with CC or failure to conceive in six ovulatory
cycles is usually followed by direct gonadotrophin stimulation
of the ovaries using a chronic low-dose protocol. This “low and
slow” protocol, starting with 25 75IU of FSH, without changing
the dose for 14 days and using only small incremental dose rises
where necessary, almost completely eliminates the danger of
OHSS and keeps the multiple pregnancy rate below 6% while
maintaining good pregnancy rates. This is achieved by steadily
reaching, but not overstepping, the threshold for a response to
FSH. If a dose increase is required, it should not be more than
half the starting dose.
A study examining the feasibility of low-dose FSH for first-line
treatment showed a clear superiority of FSH over CC. Pregnancies
and live-births were achieved more effectively and faster with
low-dose FSH than with CC, thus entertaining the possibility
that it could be used as efficient first-line treatment, cost
permitting.
109
A RANDOMIZED TRIAL OF OVULATION INDUCTION WITH TWO
DIFFERENT DOSES OF LETROZOLE IN WOMEN WITH PCOS
F. Ramezan Zadeh1 , M.M. Aghsa1 , R. Nasiri2 . 1 Vali-E-Asr
Reproductive Health Research Center, Iran, 2 Department of
Obstetrics and Gynecology, Arya Hospital, India
Objective:
To compare the effects of either a 5 mg or 7/5 mg daily dose
of letrozole in PCOS women undergoing ovulation induction and
timed intercourse.
Design:
Prospective randomized trial.
Setting:
Academic infertility care center.
Patients:
Sixty-Seven PCOS patients with infertility.
S45
Interventions:
Patients were randomly divided in to two groups and treated
with either 5 mg/day (30 patients) or 7/5 mg/day (37 patients)
letrozole for 5 days starting from day 3 of the menstrual cycle.
When the leading follicle reached 18 mm in diameter, ovulation
was triggered by an injection of HCG and timed intercourse was
advised there after.
Main outcome measures:
The number of follicles, endometrial thickness, day 7 testos-
terone level, ovulation and pregnancy rates.
Results:
The mean age, BMI, duration of infertility and basal hormone
levels in both groups were similar. There was no significant
difference in the endometrial thickness, total number of
follicles, the number of intermediate and mature follicles
on day 12 14 between the two groups. The days to reach
mature follicle were similar in both groups. Also there was
no significant difference in the day 7 testosterone level and
day 21 progesterone level between the two. Ovulation occurred
in 27 out of 30 patients (90%) in 5 mg group and 33 out
of 37 patients (89.2%) in 7.5 mg group without a statistically
significant difference. The pregnancy rate per first ovulatory
cycle was 25.8% (7/27) in 5 mg arm and 21.2% (7/33) in 7.5 mg
arm without significant difference between groups. Miscarriage
and multiple pregnancy rates were similar between them. No
OHSS was observed in either groups.
Conclusion(s):
The results of this study did not show any advantage to the use
of 7.5 mg/day over 5 mg/day dose of letrozole as the first line
treatment for induction of ovulation in women with PCOS.
110
COMPARISON OF HIGHLY PURIFIED URINARY VERSUS
RECOMBINANT FSH: EFFECT ON ART OUTCOMES IN
POLYCYSTIC OVARY SYNDROME
F. Sohrabvand, S.H. Sheikhhassani, M. Bagheri, F. Hagollahi.
Vali-e-Asr Hospital, Tehran University of Medical Sciences,
Infertility Department, Tehran, Iran
Introduction:
Polycystic ovary syndrome is a common cause of ovulatory
disorders and infertility with high LH to FSH ratio. in order to
prevent further increase of LH and folliclar atresia, different
regimens for ovulation induction have been recommended using
FSH alone. This study was performed in PCOS patients to compare
ART outcomes in cycles induced by FSH alone, using either
recombinant or urinary products.
Materials and Methods:
In a randomized trial, from 623 patients who underwent down
regulation with GnRH analogue in a long protocol, 160 PCOS
patients were randomly divided into two groups of 80. Group A
received 150 IU/d recombinant FSH (Gonal-F) and group B
150 IU/d urinary FSH (Fostimon).
Results:
33 cases (41.2%) in group A and 36 (45%) in group B
achieved clinical pregnancy, which was not significantly different
(p = 0.67). Total number of oocytes retrieved (13.03±5.56
vs 14.17±4.89, p = 0.17), quality and number of embryos
(7.42±3.35 vs 7.63±3.28, p = 0.68)and OHSS rate were similar
in group A compared to group B. Endometrial thickness, which
was 9.66±1.67 mm in group A and 10.36±1.35 mm in group B,
showed a significant difference (p = 0.004).
Conclusion:
It seems that in PCOS patients, both pure FSH products used for
controlled ovarian hyperstimulation have similar effects on ART
outcome and can be used according to availability and patient
acceptance without significant difference.