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PREVENTION OF OVARIAN
Rizk (1993a, b) suggested the ÔÇ˜ÔÇ˜Ten CommandmentsÔÇ™ÔÇ™ for the prevention
of OHSS. Today, the list has expanded to two lists of ÔÇ˜ÔÇ˜Ten CommandmentsÔÇ™ÔÇ™.
The ´¬ürst list addresses the primary prevention of OHSS, which include options
before stimulation, such as ovarian diathermy, and during stimulation, such as
using low-dose gonadotrophins (Figure VII.1). The second list addresses
the secondary prevention of OHSS, which includes withholding or delaying
hCG, use of a LH or GnRH agonist in place of hCG for triggering ovulation and
progesterone for luteal phase support (Figure VII.2).
PRIMARY PREVENTION OF OHSS
Identification of Patients at Risk of OHSS before Stimulation
It would be impossible to completely prevent OHSS without careful assessment
of patients to identify those who are at signi´¬ücant risk (Rizk and Abdalla, 2006).
I cannot overemphasize the role of the tools used for prediction to be able to
achieve primary prevention of OHSS.
Fig. VII.1: Primary prevention of OHSS
STIMULATION PROTOCOLS TO AVOID OHSS
Fig. VII.2: Secondary prevention of OHSS: the ÔÇ˜ÔÇ˜Ten CommandmentsÔÇ™ÔÇ™
Fig. VII.3: Ovulation induction in PCOS patients
STIMULATION PROTOCOLS TO AVOID OHSS
Prevention of OHSS in PCOS Patients
Rizk and Smitz (1992) highlighted that ovarian stimulation for patients with
PCOS carries the highest risk for development of the severe forms of OHSS.
Similar observations have been made by almost all investigators over the last
decade (MacDougall et al., 1993; Delvigne et al., 1993; Aboulghar et al., 1996a).
Today, this is one of the major challenges in PCOS patients. Several approaches
have been used (Figure VII.3) starting with such lifestyle modi´¬ücations as
weight loss and metformin treatment, moving on to low-dose gonadotropins
and ending with laparoscopic ovarian drilling and assisted reproductive
technology (ART) (Rizk, 1992, 1993a, 2001, 2002).
132 PREVENTION OF OVARIAN HYPERSTIMULATION SYNDROME
Lifestyle Modification in PCOS patients
A recent pilot prospective randomized placebo-controlled trial on the effect of
lifestyle modi´¬ücation and metformin therapy on ovulation and androgen
concentration in women with PCOS was performed (Hoeger et al., 2004).
In the study, 30 overweight or obese women with PCOS were randomized to
one of four 48-week interventions. The interventions were: metformin, 850 mg
two times per day; lifestyle modi´¬ücation plus metformin, 850 mg two times per
day; lifestyle modi´¬ücation plus placebo; or placebo alone. The authors conclu-
ded that weight reduction might play the most signi´¬ücant role in the restoration
of ovulation in obese women with PCOS.
Low-dose Gonadotrophins in PCOS Patients
LOW-DOSE OVARIAN STIMULATION IN NON-IVF CYCLES
Prevention of OHSS in this group of patients is rather dif´¬ücult because of the
narrow margin between the dose required to induce reasonable stimulation
and the dose that may result in the development of OHSS (Figure VII.4). The
original work on the low-dose protocol was reported by Seibel et al. (1984)
in Boston and was soon followed by ´¬üne modi´¬ücations of the dose and
the protocol. The low-dose gonadotropin protocol was successfully used in
the treatment of patients with PCOS to achieve satisfactory ovulation and
pregnancy rates and reduce the risk of developing OHSS (Seibel et al., 1984;
Polson et al., 1987; Buvat et al., 1989; Shoham et al., 1991; Homburg et al.,
1995; Rizk and Thorneycroft, 1996).
Both low-dose step-up (Figure VII.5) and step-down protocols
(Figure VII.6) have been used with similar ovulation and pregnancy rates
and OHSS rates (Table VII.1). Two randomized trials comparing the low-dose
step-up with the low-dose step-down protocol have demonstrated similar
successful results (Table VII.2).
LOW-DOSE FSH IN PCOS
The induction of ovulation was reported successfully using recombinant FSH
in patients with PCOS (Hornnes et al., 1993). Hedon et al. (1998) found
signi´¬ücantly fewer follicles larger than 10 mm and a lower estradiol level in the
chronic low-dose compared with the conventional regimen. Aboulghar et al.
(1996b) compared the low-dose recombinant FSH and hMG protocols in
the treatment of patients with a history of severe OHSS. The recombinant
FSH low-dose protocol proved to be as effective as the low-dose hMG protocol
in producing reasonable ovulation and pregnancies in PCOS patients with
a history of severe OHSS; the protocol was safe with regard to the risk of
developing OHSS. Rosenwaks (2003) highly recommended a very gentle stimu-
lation approach as the key component of prevention of OHSS. This involves
lower gonadotrophin dosage and hCG dosage as well. Bayram et al. (2001)
performed a meta-analysis on the safety and effectiveness in terms of ovulation,
pregnancy, multiple pregnancy, miscarriage, and OHSS of recombinant FSH
STIMULATION PROTOCOLS TO AVOID OHSS
Fig. VII.4: Conceptualized model of granulosa cell responses to a range of follicle
stimulating hormone (FSH) doses administered during ovulation induction in normal
women (A) and women with PCOS (B)
Reproduced with permission from Chang (2004). In (Strauss, Barbieri, Eds), Yen and JaffeÔÇ™s
Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management, 5th ed.
Philadelphia: Elsevier, Saunders, Chapter 19, p. 613
Fig. VII.5: Continuous low-dose step-up protocol (adapted from Macklon et al., 1999)
Reproduced with permission from Edwards and Risquez (Eds) (2003). Modern Assisted
Conception, Reproductive Biomedicine Online: Reproductive Healthcare Ltd, p. 98
134 PREVENTION OF OVARIAN HYPERSTIMULATION SYNDROME
Fig. VII.6: Continuous low-dose step-down protocol (adapted from Macklon et al., 1999)
Reproduced with permission from Edwards, Risquez (Eds) (2003). Modern Assisted
Conception, Reproductive Biomedicine Online: Reproductive Healthcare Ltd, p. 98.
Table VII.1 Comparison of ovarian response and clinical outcome following the
low-dose step-up and step-down regimens for gonadotropin induction of
Reproduced with permission from Fauser and Macklon (2004). Medical
approaches to ovarian stimulation for infertility. In (Strauss, Barbieri, Eds),
Yen and JaffeÔÇ™s Reproductive Endocrinology. Philadelphia: Elsevier, Saunders,
Chapter 31, pp. 965ÔÇ“1012
Low-dose step-up Step-down
Hamilton-Fairley Hull Balen et al. Van Santbrink
(1991) (1991) (1994) et al. (1995)
No. patients 100 144 103 82
No. cycles 401 459 603 234
Duration of treatment (days) 14 NR* NR 11
Ampules per cycle 19 NR NR 14
Ovulation rate (%) 72 74 68 91
% ovulatory cycles 73 NR NR 62
% of all started cycles 55 NR NR 56
per started cycle 11 11 14 16
per ovulatory cycle 16 15 20 17
Cumulative pregnancy rate (%) 55 NR 73 47
Multiple pregnancy rate (%) 4 11 18 8
Ongoing singleton pregnancy rate (%) 7 10 9 12
OHSS rate (%) 1 NR 1 2
* NR ┬╝ not recorded
STIMULATION PROTOCOLS TO AVOID OHSS
Table VII.2 Randomized studies comparing the low-dose step up with the
step-down protocol for ovulation induction
Reproduced with permission from Fauser and Macklon (2004). In (Strauss,
Barbieri, Eds), Yen and JaffeÔÇ™s Reproductive Endocrinology, 5th ed. Philadelphia:
Elsevier and Saunders, Chapter 31, pp. 965ÔÇ“1012
Van Santbrink and Christin-Maitre and
Fauser (1997) Hughes(2003)
Step-up Step-down p-value Step-up Step-down p-value
Median duration of treatment (days) 18 9 0.003 15 10 <0.001
Monofollicular growth 56% 88% 0.04 68% 32% <0.0001
Overall ovulation rate 84% 89% NS* 70% 61% <0.02
* NS ┬╝ not signi´¬ücant
(rFSH) versus urinary FSH (uFSH) in women with clomiphene-resistant PCOS.
Four randomized trials comparing rFSH vs. uFSH were identi´¬üed and no
signi´¬ücant differences were demonstrated for the outcome. The odds ratio for
the ovulation rate was 1.19 (95% con´¬üdence interval (CI), 0.78ÔÇ“1.80),
pregnancy rate 0.95 (95% CI, 0.64ÔÇ“1.41), miscarriage rate 1.26 (95% CI,
0.59ÔÇ“2.70), multiple pregnancy rate 0.44 (95% CI, 0.16ÔÇ“1.21) and OHSS 1.55
(95% CI, 0.50ÔÇ“4.84). Similarly, in the only randomized trial that compared
chronic low-dose vs. conventional regimen with rFSH, no signi´¬ücant differ-
ences were found.
LOW-DOSE OVARIAN STIMULATION FOR IVF
If ovarian hyperstimulation is performed for IVF, it is recommended to start
with lower doses of hMG or FSH if the patient has had previous OHSS or is
at high risk (Rizk et al., 1991a, b; Marci, 2001). In general, the starting dose of
gonadotrophins in the United States is higher than the starting dose in Europe
(Rizk, 2001, 2002). A useful example to illustrate this concept (Figure VII.7)
was presented by Professor Johan Smitz from Belgium to demonstrate the
impact of lowering the dose (Rizk and Smitz, 1992). It must be mentioned that
lowering the dose could in some cases result in an unsuccessful IVF cycle so the
situation is more dif´¬ücult than ovarian stimulation without IVF.
In general, we recommend starting at a dose of 150 IU/day for IVF
stimulation in young PCOS patients. If the patients have become hyperstimu-
lated on this dose in a previous cycle, we would start at 100ÔÇ“112.5 IU/day. If the
patient is 40 years old or older, we recommend a starting dose of 225 IU/day,
and to consider reducing the dose to 150 IU/day.
LIMITED OVARIAN STIMULATION
A different approach whereby the hCG was administered when the leading
follicle reached a diameter of 12 mm was reported by El-Sheikh et al. (2001).
In a prospective study, with the patients serving as their own control,
136 PREVENTION OF OVARIAN HYPERSTIMULATION SYNDROME
Fig. VII.7: Low-dose gonadotropins may help in prevention of OHSS
Reproduced with permission from Rizk and Smitz (1992). Hum Reprod 7:320ÔÇ“7
20 patients with a history of severe OHSS have undergone a second IVF cycle
with what is termed as ÔÇ˜ÔÇ˜limited ovarian stimulation.ÔÇ™ÔÇ™ All patients produced
mature oocytes and fertilization and eight clinical pregnancies were achieved.
None of the patients experienced symptoms of severe OHSS or required
STIMULATION PROTOCOLS TO AVOID OHSS
Table VII.3 Meta-analysis of metformin for
ovulation induction in PCOS
Reproduced with permission from Lord et al.
(2003). Cochrane database systematic review
Odds ratios intervals
Metformin versus placebo
ovulation rate 3.8 2.3ÔÇ“6.7*
pregnancy rate 2.8 0.9ÔÇ“9.0
Metformin and CC** versus CC alone
ovulation rate 4.4 2.4ÔÇ“8.2*
pregnancy rate 4.4 2.0ÔÇ“9.9
* Statistically signi´¬ücant difference
** CC ┬╝ clomiphene citrate
Metformin in PCOS Patients
Metformin is widely used for the treatment of insulin resistance in women
with PCOS. A Cochrane review (Table VII.3), based on 14 randomized clinical
trials, including 543 human subjects with biochemical and/or ultrasound evi-
dence for PCOS, was recently published (Lord et al., 2005). DeLeo et al. (1999)
performed a prospective randomized trial on 21 women with clomiphene-
resistant PCOS which demonstrated that metformin use results in a reduction
of intra-ovarian androgens by reducing hyperinsulinism. This leads to a reduc-
tion in estradiol and favors orderly follicular growth in response to exogenous
gonadotrophins. Therefore, it is possible that in obese PCOS patients under-
going IVF, the addition of metformin might decrease the incidence of OHSS.
Aromatase Inhibitors in PCOS Patients
Aromatase inhibitors have been successfully used for ovulation induction in
women with polycystic ovarian syndrome (Mitwally and Casper, 2000, 2001).
The favorable pregnancy outcome and low multiple gestation rate of aromatase
inhibitors for ovarian stimulation is encouraging for the development of
these agents as ´¬ürst-line ovulation induction agents (Mitwally et al., 2005).
However, there has been recent concern about anomalies in pregnancies
following cycles where aromatase inhibitors were used.
Ketoconazole in PCOS Patients and OHSS
Parsanezhad et al. (2003) performed a prospective randomized double-blind,
placebo-controlled trial to evaluate the role of ketoconazole in the prevention
of OHSS in PCOS women undergoing ovarian stimulation with gonadotro-
phins at Shiraz University, Iran. Fifty patients were randomly assigned to
138 PREVENTION OF OVARIAN HYPERSTIMULATION SYNDROME
receive two ampoules of hMG on day two or three of the cycle and
ketoconazole, 50 mg every 48 h starting on the ´¬ürst day of hMG treatment, and
51 patients received hMG plus placebo tablets. Ketoconazole did not prevent
OHSS in patients with PCOS undergoing ovarian stimulation. It reduced the
rate of folliculogenesis and steroidogenesis.
OCTREOTIDE AND OHSS
Morris et al. (1999) performed a prospective double-blind, placebo-controlled
crossover trial to determine whether octreotide is effective for ovulation induc-
tion and/or prevention of OHSS in PCOS patients with clomiphene resistance.
Octreotide was no more effective than placebo for clomiphene-resistant pati-
ents; however, it reduced estradiol levels and number of follicles when combined
with urinary FSH. No cases of OHSS occurred in either group. The authors
concluded that octreotide may reduce the incidence of OHSS in PCOS patients.
Pentoxifylline in the Prevention of OHSS
Pentoxifylline is a methylxanthine phosphodiesterase inhibitor that has been
utilized in a variety of areas in assisted reproductive technology (Yovich, 1993;
Rizk et al., 1995; Fountain et al., 1995). Pentoxifylline inhibits tumor necrosis
factor alpha synthesis. Serin et al. (2002) conducted a study into whether
pentoxifylline would prevent OHSS in the rabbit model. Despite an observed
decrease in ovarian weight and number of ovulations in OHSS in the rabbit
model, pentoxifylline did not prevent ascites formation.
LAPAROSCOPIC OVARIAN DRILLING IN
Laparoscopic ovarian drilling has been used successfully for prevention of
OHSS in patients with polycystic ovaries (Rizk and Nawar, 2001). Both ovarian
diathermy and laser vaporization have been used immediately prior to the
commencement of ovarian stimulation in patients at risk of OHSS. Ovarian
diathermy has been performed in either one or both ovaries (Figure VII.8).
Transvaginal ovarian drilling has also been reported in patients with PCOS