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Lass A, Vassiliev A, Decosterd G et al. (2002). Relationship of baseline ovarian volume to
ovarian response in World Health Organization Group II anovulatory patients who
underwent ovulation induction with gonadotropins. Fertil Steril 78:265À9.
Ludwig M, Jelkmann W, Bauer O et al. (1999). Prediction of severe ovarian hyper-
stimulation syndrome by free serum vascular endothelial growth factor concentra-
tion on the day of human chorionic gonadotrophin administration. Hum Reprod
14:2437À41.
Mathur R, Hayman G, Bansal A et al. (2002). Serum vascular endothelial growth factor
levels are poorly predictive of subsequent ovarian hyperstimulation syndrome in
highly responsive women undergoing assisted conception. Fertil Steril 78:1154À58.
Moohan JM, Curcio K, Leoni M et al. (1997). Low intraovarian vascular resistance: a
marker for severe ovarian hyperstimulation syndrome. Fertil Steril 57:728À32.
Morris RS, Paulson RJ, Sauer MV et al. (1995). Predictive value of serum oestradiol
concentrations and oocyte number in severe ovarian hyperstimulation syndrome.
Hum Reprod 10:811À14.
Ogawa S, Minakami H, Araki S et al. (2001). A rise of the serum level of von Willebrand
factor occurs before clinical manifestation of the severe form of ovarian
hyperstimulation syndrome. J Assist Reprod Genet 18:114À19.
Pellicer A, Albert C, Mercader A et al. (1999). The pathogenesis of ovarian
hyperstimulation syndrome: in vivo studies investigating the role of interleukin-1b,
interleukin-6 and vascular endothelial growth factor. Fertil Steril 71:482À9.
Quintana R, Kopcow L, Marconi G et al. (2001). Relationship of ovarian stimulation
response with vascular endothelial growth factor and degree of granulosa cell
apoptosis. Hum Reprod 16:1814À18.
Rizk B (1992). Ovarian hyperstimulation syndrome. In (Brinsden PR, Rainsbury PA, Eds),
A Textbook of In-vitro Fertilization and Assisted Reproduction. Carnforth, UK:
Parthenon Publishing, pp. 369À83.
Rizk B (1993). Ovarian hyperstimulation syndrome. In (Studd J, Ed.), Progress in
Obstetrics and Gynecology. Edinburgh: Churchill Livingstone, Vol.11, Chapter 18,
pp. 311À49.
Rizk B (2001). Ovarian hyperstimulation syndrome: prediction, prevention and manage-
ment. In (Rizk B, Devroey P, Meldrum DR, Eds), Advances and Controversies In
Ovulation Induction. 34th ASRM Annual Postgraduate Program, Middle East Fertility
Society Precongress Course. ASRM, 57th Annual Meeting, Orlando, FL, pp. 23À46.
Published by the American Society for Reproductive Medicine.
Rizk B (2002). Can OHSS in ART be eliminated? In (Rizk B, Meldrum D, Schoolcraft W,
Eds), A Clinical Step-by-Step Course for Assisted Reproductive Technologies. 35th
ASRM Annual Postgraduate Program, Middle East Fertility Society Precongress
Course. ASRM, 58th Annual Meeting, Seattle, WA, pp. 65À102. Published by the
American Society for Reproductive Medicine.
Rizk B & Aboulghar M (1991). Modern management of ovarian hyperstimulation
syndrome. Hum Reprod 6:1082À7.
Rizk B & Aboulghar MA (2005). Classi¬cation, pathophysiology and management of
ovarian hyperstimulation syndrome. In (Brinsden P, Ed.), A Textbook of In-vitro
Fertilization and Assisted Reproduction, Third Edition. London: Parthenon Publishing,
Chapter 12, pp. 217À58.
Rizk B & Nawar MG (2004). Ovarian Hyperstimulation Syndrome. In (Serhal P,
Overton C, Eds), Good Clinical Practice in Assisted Reproduction. Cambridge, UK:
Cambridge University Press, Chapter 8, pp. 146À66.
Rizk B & Smitz J (1992). Ovarian hyperstimulation syndrome after superovulation for IVF
and related procedures. Hum Reprod 7:320À7.
129
REFERENCES




Rizk B, Aboulghar MA, Smitz J et al. (1997). The role of vascular endothelial growth factor
and interleukins in the pathogenesis of severe ovarian hyperstimulation syndrome.
Hum Reprod Update 3:255À66.
Smith BH & Cooke ID (1991). Ovarian hyperstimulation: actual and theoretical risks.
Comment. BMJ 302:127À8.
Tal J, Faz B, Samberg I et al. (1985). Ultrasonographic and clinical correlates of
menotrophin versus sequential clomiphene citrate: menotrophin therapy for
induction of ovulation. Fertil Steril 45:342À9.
Thomas K, Searle T, Quinn A et al. (2002). The value of routine estradiol monitoring in
assisted conception cycles. Acta Obstet Gynecol Scand 81:554À5.
Todorow S, Schricker S, Siebzehnruebl E et al. (1993). Von Willebrand factor: an
endothelial marker to monitor in-vitro fertilization patients with ovarian hyper-
stimulation syndrome. Hum Reprod 8:2039À46.
Tozer AJ, Iles RK, Iammarrone E et al. (2004). The effects of ˜coasting™ on follicular ¬‚uid
concentrations of vascular endothelial growth factor in women at risk of developing
ovarian hyperstimulation syndrome. Hum Reprod 19:522À8.
VII

PREVENTION OF OVARIAN
HYPERSTIMULATION SYNDROME


Rizk (1993a, b) suggested the ˜˜Ten Commandments™™ for the prevention
of OHSS. Today, the list has expanded to two lists of ˜˜Ten Commandments™™.
The ¬rst 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¬cant 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




130
131
STIMULATION PROTOCOLS TO AVOID OHSS




Fig. VII.2: Secondary prevention of OHSS: the ˜˜Ten Commandments™™




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¬cations 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¬cation 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¬cation plus metformin, 850 mg two times per
day; lifestyle modi¬cation plus placebo; or placebo alone. The authors conclu-
ded that weight reduction might play the most signi¬cant 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¬cult 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 ¬ne modi¬cations 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¬cantly 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
133
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 Jaffe™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
ovulation
Reproduced with permission from Fauser and Macklon (2004). Medical
approaches to ovarian stimulation for infertility. In (Strauss, Barbieri, Eds),
Yen and Jaffe™s Reproductive Endocrinology. Philadelphia: Elsevier, Saunders,
Chapter 31, pp. 965“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
Monofollicular cycles:
% ovulatory cycles 73 NR NR 62
% of all started cycles 55 NR NR 56
Pregnancy rate
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 ¼ not recorded
135
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 Jaffe™s Reproductive Endocrinology, 5th ed. Philadelphia:
Elsevier and Saunders, Chapter 31, pp. 965“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 ¼ not signi¬cant


(rFSH) versus urinary FSH (uFSH) in women with clomiphene-resistant PCOS.
Four randomized trials comparing rFSH vs. uFSH were identi¬ed and no
signi¬cant differences were demonstrated for the outcome. The odds ratio for
the ovulation rate was 1.19 (95% con¬dence interval (CI), 0.78“1.80),
pregnancy rate 0.95 (95% CI, 0.64“1.41), miscarriage rate 1.26 (95% CI,
0.59“2.70), multiple pregnancy rate 0.44 (95% CI, 0.16“1.21) and OHSS 1.55
(95% CI, 0.50“4.84). Similarly, in the only randomized trial that compared
chronic low-dose vs. conventional regimen with rFSH, no signi¬cant 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¬cult 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 100“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 7:320“7



20 patients with a history of severe OHSS have undergone a second IVF cycle
with what is termed as ˜˜limited ovarian stimulation.™™ All patients produced
mature oocytes and fertilization and eight clinical pregnancies were achieved.
None of the patients experienced symptoms of severe OHSS or required
hospitalization.
137
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

95% con¬dence
Odds ratios intervals

Metformin versus placebo
ovulation rate 3.8 2.3“6.7*
pregnancy rate 2.8 0.9“9.0
Metformin and CC** versus CC alone
ovulation rate 4.4 2.4“8.2*
pregnancy rate 4.4 2.0“9.9

* Statistically signi¬cant difference
** CC ¼ 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 ¬rst-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 ¬rst 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
PCOS PATIENTS

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

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