LINEBURG


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Are There Other Effects of the FSH Receptor Mutations
Kaiser (2003) discussed three interesting possible effects of the FSH receptor
mutations identi¬ed in association with spontaneous OHSS. The ¬rst
possibility is that such mutations may lead to increased susceptibility to
iatrogenic OHSS in patients undergoing ovulation induction. The second
predisposition is multiple pregnancy as a result of increased stimulation of
ovarian follicular development. However, in the three reported cases, no
multiple pregnancies were observed. Finally, there is an unresolved concern that
ovulation induction may increase the risk of cancer of the ovary, breast or
uterus. Therefore, patients with activating mutations of the FSH receptor
require careful and diligent follow-up, perhaps for a long time (Kaiser, 2003).


SPONTANEOUS AND IATROGENIC OHSS

The recent identi¬cation of mutations in the FSH receptor gene which display
an increased sensitivity to hCG and are responsible for the development of
88 GENETICS OF OVARIAN HYPERSTIMULATION SYNDROME




spontaneous OHSS, provides for the ¬rst time the molecular basis for the
physiopathology of spontaneous OHSS (Delbaere et al., 2004; Rizk and
Aboulghar, 2005). In the three reported cases, the abnormal function of mutant
FSH receptors in vitro provides a reasonable explanation for their implication
of their role in OHSS development in vivo. During pregnancy there is a
signi¬cant decrease in the FSH receptor expression in the corpus luteum.
However, the expression of FSH receptor in the granulosa cells of the
developing follicles remains constant (Simoni et al., 1997). Since the pituitary
gonadotrophins fall to very low levels in the serum, these receptors are not
usually stimulated during pregnancy (Delbaere et al., 2004). The mutant FSH
receptor expressed in the developing follicles could be stimulated by the
pregnancy-derived hCG and the follicle would start growing and enlarge.
Finally, the granulosa cells acquire LH receptors which may also be stimulated
by hCG (Delbaere et al., 2004). This would induce follicular luteinization and
secretion of vasoactive substances that is implicated in the pathophysiology of
the syndrome.
The interaction between the FSH receptor and hCG is therefore a
requirement for the development of spontaneous OHSS. Delbaere et al. (2004)
highlighted the differences between spontaneous and iatrogenic OHSS, and
proposed a model to account for the different chronology between the two
forms of the syndrome (Figure IV.10). In the iatrogenic form, the follicular
recruitment and enlargement occur during ovarian stimulation with exogenous
FSH (Dahl Lyons et al., 1994), while in the spontaneous form, the follicular
recruitment occurs later through the stimulation of the FSH receptor by
pregnancy-derived hCG. In both forms, massive luteinization of enlarged
stimulated ovaries ensues, inducing the release of vasoactive mediators, leading
to the development of the symptoms of OHSS. It is possible that the
stimulation of the mutated FSH receptor occurs at the threshold hCG level.
That threshold value could vary according to the type of mutation. In the ¬rst
trimester of pregnancy, hCG peaks between 8 and 10 weeks and declines
thereafter. It follows therefore that the initiation of follicular growth by
pregnancy-derived hCG could start between 6 and 10 weeks of amenorrhea
(Delbaere et al., 2004). If these follicles develop at the same rate as ovarian
stimulation, the development of OHSS will occur at the time of massive
follicular luteinization, between 8 and 12 weeks amenorrhea (Figure IV.10).


PREDICTION OF SEVERITY OF SYMPTOMS IN
IATROGENIC OHSS BY FSH RECEPTOR POLYMORPHISM

The potential association of the S680 allele with poor responders to ovarian
stimulation for IVF (Perez Mayorga et al., 2000; DeCastro et al., 2003) led to
the hypothesis that the N680 allele could be associated with hyper-responders,
i.e. patients at risk of iatrogenic OHSS. In an elegant study published by
Daelemans et al. (2004), no statistically signi¬cant differences were found in
allelic and genotypic frequencies between the IVF control population and the
89
RECURRENT THYROTOXOCOSIS IN PREGNANCY




Fig. IV.10: Chronological development of iatrogenic and spontaneous OHSS
Reproduced with permission from Delbaere et al. (2004). Hum Reprod 19:486À9



OHSS patients. However, Daelemans et al. (2004) observed a signi¬cant
enrichment in allele 680 as the severity of OHSS increased (p ¼ 0.034). The
authors suggested that the genotype in position 680 of the FSH receptor cannot
predict which patient will develop OHSS, but could be a predictor of severity of
OHSS symptoms among OHSS patients.


RECURRENT THYROTOXOCOSIS IN PREGNANCY DUE
TO THYROTROPIN RECEPTOR MUTATION

A similar phenomenon has been described by Rodien et al. (1998), in which
stimulation of the thyrotropin receptor occurred by chorionic gonadotrophin.
A woman and her mother had recurrent gestational hyperthyroidism despite
normal serum chorionic gonadotrophin concentration. Both women were
heterozygous for missense mutation in the extracellular domain of the
thyrotropin receptor. The mutant receptor was more sensitive than the wild-
type receptor to hCG, thereby explaining the occurrence of hyperthyroidism
despite the fact that chorionic gonadotrophin concentrations were low. The
major difference between this case and the three cases of FSH receptor
90 GENETICS OF OVARIAN HYPERSTIMULATION SYNDROME




mutation is in the position of the amino acid substituted. The substitution of
arginine for lysine is in a region of a receptor that constitutes the surface of
interaction with thyrotropin, and arginine at position 183 may increase the
stability of the illegitimate complex between hCG and thyrotropin receptor
enough to cause signal transduction by the increased serum hCG concentra-
tions present in pregnant women (Rodien et al., 1998).


REFERENCES

Aittomaki K, Dieguez-Lucena JI, Pakarinen P et al. (1995). Mutation in the follicle-
stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian
failure. Cell 82:959À68.
Daelemans C, Smits G, de Maerlelaer V et al. (2004). Prediction of severity of symptoms in
iatrogenic ovarian hyperstimulation syndrome by follicle stimulating hormone
receptor Ser680Asn polymorphism. J Clin Endocrinol Metab 89:6310À15.
Dahl Lyons CA, Wheeler CA, Frishman GN et al. (1994). Early and late presentation
of the ovarian hyperstimulation syndrome: two distinct entities with different risk
factors. Hum Reprod 9:792À9.
De Castro R, Ruiz R, Montoro L et al. (2003). Role of follicle-stimulating hormone
receptor Ser680Asn polymorphism in the ef¬cacy of follicle stimulating hormone.
Fertil Steril 80:571À6.
Delbaere A, Smits G, Olatunbosun O et al. (2004). New insights into the pathophysiology
of ovarian hyperstimulation syndrome. What makes the difference between
spontaneous and iatrogenic syndrome? Hum Reprod 19:486À9.
Edwards RG & Rizquez F (Eds) (2003). Modern Assisted Conception. Cambridge UK:
Biomedicine Online: Reporoductive Healthcare Ltd, pp. 66À70.
Gromoll J, Ried T, Holtgreve-Grez H, Nieschlag E et al. (1994). Localization of the
human FSH receptor to chromosome 2p21 using a genomic probe comprising
exon 10. J Mol Endocrinol 12:265À71.
Gromoll J, Simoni M & Nieschlag E (1996). An activating mutation of the follicle-
stimulating hormone receptor autonomously sustains spermatogenesis in a
hypophysectomized man. J Clin Endocrinol Metab 81:1367À70.
Kaiser UB (2003). The pathogenesis of the ovarian hyperstimulation syndrome. N Engl J
Med 349:729À32.
Laven JS, Mulders AG, Suryandari DA et al. (2003). Follicle stimulationg hormone
receptor polymorphisms in women with normogonadotrophic anovulatory infertil-
ity. Fertil Steril 80:986À92.
Montanelli L, Van Durme JJ, Smits G et al. (2004a). Modulation of ligand selectivity
associated with activation of the transmembrane region of the human follitropin
receptor. Mol Endocrinol 18:2061À73.
Montanelli L, Delbaere A, Di Carlo C et al. (2004b). A mutation in the follicle-stimulating
hormone receptor as a cause of familial spontaneous ovarian hyperstimulation
syndrome. J Clin Endocrinol Metab 89:1255À8.
Olijve W, de Boer W, Mulders JWM et al. (1996). Molecular biology and biochemistry
of human recombinant folicle stimulationg hormone (Puregon• ). Mol Hum Reprod
2:371À82.
Perez Mayorga M, Gromoll J, Behre HM et al. (2000). Ovarian response to follicle
stimulating hormone (FSH) stimulation depends on the FSH receptor genotype.
J Clin Endocrinol Metab 85:3365À9.
Rizk B & Abdalla H (2006). Reproductive physiology of the female. In (Rizk B, Abdalla H,
Eds), Infertility and Assisted Reproduction Technology. Oxford, UK: Health Press,
pp. 8À12.
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REFERENCES




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.
Rodien P, Bemont C & Sanson ML (1998). Familial gestational hyperthyroidism caused
by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotrophin.
N Eng J Med 339:1823À6.
Rousseau-Merck MF, Atger M, Loosfelt H et al. (1993). The chromosomal localization
of the human follicle-stimulating hormone receptor (FSHR) gene on 2p21-p16 is
similar to that of the luteinizing hormone receptor gene. Genomics 15:222À4.
Simoni M, Gromoll J & Nieschlag E (1997). The follicle stimulating hormone receptor:
biochemistry, molecular biology, physiology, and pathophysiology. Endocr Rev
18:739À73.
Simoni M, Nieschlag E & Gromoll J (2002). Isoforms and single nucleotide
polymorphisms of the FSH receptor gene: Implications for human reproduction.
Hum Reprod Update 8:413À21.
Smits G, Olatunbosun O, Delbaere A et al. (2003). Ovarian hyperstimulation syndrome
due to a mutation in the follicle-stimulating hormone receptor. N Eng J Med
349:760À6.
Sprengel R, Braun T, Nikolics K et al. (1990). The testicular receptor for follicle
stimulating hormone: structure and functional expression of cloned cDNA. Mol
Endocrinol 4:525À30.
Sudo S, Kudo M, Wada S et al. (2002). Genetic and functional analyses of polymorphisms
in the human FSH receptor gene. Mol Hum Reprod 8:893À9.
Themmen HPN & Huhtaniemi IT (2000). Mutations of gonadotrophins and
gonadotrophin receptors: elucidating the physiology and pathophysiology of
pituitary-gonadal function. Endocr Rev 21:551À83.
Vasseur C, Rodien P, Beau I et al. (2003). A chorionic gonadotrophin-sensitive mutation
in the follicle-stimulating hormone receptor as a cause of familial gestational
spontaneous ovarian hyperstimulation syndrome. N Engl J Med 349:753À9.
Vlaeminck-Guillem V, Ho SC, Rodien P et al. (2002). Activation of the cAMP pathway
by the TSH receptor involves switching of the ectodomain from a tethered inverse
agonist to an agonist. Mol Endocrinol 16:736À46.
Whithney EA, Layman LC, Chan PJ et al. (1995). The follicle-stimulating hormone
receptor gene is polymorphic in premature ovarian failure and normal controls.
Fertil Steril 64:518À24.
V

COMPLICATIONS OF OVARIAN
HYPERSTIMULATION SYNDROME


Complications of OHSS are well documented in the literature (Rizk, 1992,
1993a; Bergh and Lundkvist, 1992; Roest et al., 1996). Bergh and Lundkvist
(1992) surveyed the 12 IVF clinics in the Nordic countries and documented
OHSS requiring hospital care in 0.7% of 10 125 treatment cycles. Similarly,
Roest et al. (1996) performed a retrospective analysis of 2,495 cycles at the
single clinic in The Netherlands. Hospital admission was required in 0.7% of
cycles due to severe OHSS. While vascular complications are the most dreaded,
other complications, such as pulmonary, gastrointestinal and renal complica-
tions have very serious sequelae in severe cases (Rizk and Nawar, 2004; Rizk and
Aboulghar, 2005).


FATAL CASES OF OVARIAN HYPERSTIMULATION
SYNDROME

Since the introduction of gonadotrophins for ovulation induction, there have
been a number of deaths directly and indirectly related to OHSS (Schenker
and Weinstein, 1978). The incidence of mortality following OHSS has been
estimated at 1 in 500 000 (Brinsden et al., 1995). In three large reports of IVF
from the Nordic countries, The Netherlands and Australia, there have been no
reports of death in 10 125, 2495 and 59 681 IVF treatment cycles, respectively
(Bergh and Lundkvist, 1992; Roest et al., 1996; Venn et al., 2001). It is also
reassuring that the Australian registry showed that the mortality in a cohort of
IVF patients is signi¬cantly lower then that in the general female population
of the same age (age standardized mortality ratio of 0.58 and 95%, con¬dence
interval 0.48À0.65, Venn et al., 2001).
The ¬rst fatal cases were described in 1951 by Gotzsche (Esteban-Altirriba,
1961) and also in 1958 (Figueroa-Casas, 1958). Until 1961, 60 cases of hyper-
stimulation have been reported including two deaths in patients treated with
pregnant mare serum gonadotrophins (PMSG) (Figueroa-Casas, 1958; Muller,
1962; Schenker and Weinstein, 1978).
Lunenfeld (1963) ¬rst reported on the use of human menopausal
gonadotrophins for ovulation induction. Over the last four decades there
have been a handful of reports of death due to OHSS but the majority of




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FATAL CASES OF OVARIAN HYPERSTIMULATION SYNDROME




cases are not reported (Mozes et al., 1965; Cluroe and Synek, 1995; Beerendonk
et al., 1998; Serour et al., 1998; Semba et al., 2000). These cases are extremely
important from a clinical viewpoint, and therefore they deserve special
mention.
Mozes et al. (1965) reported a patient™s demise as a result of arterial
thromboembolism associated with OHSS. The patient was 37 years old and had
been treated for infertility. She was in a concentration camp during the war
years. At that time, menstruation ceased and did not reappear until she reached
the age of 17 in 1945. She got married at the age of 20 and a year later gave
birth at full term following a normal pregnancy. She had amenhorrea and
galactorrhea after her pregnancy and she was diagnosed with ChiariÀFrommel
syndrome. In 1964, she was treated with 28 ampoules of gonadotrophin therapy
(Pergonal-500) using 2À3 ampoules per day, each containing 500 units
of gonadotrophins. This treatment was followed by 30 000 IU of hCG. She
became pregnant but had a missed abortion. A year later, she was treated with
60 ampoules of gonadotrophin using the same schedule of 2À3 ampoules
per day. This time she was given 25 000 IU of hCG and she presented to
the hospital with acute left hemiplegia, in shock and comatose, and had
an occlusion of the left internal carotid artery. She died in the hospital the
following day.
Cluroe and Synek (1995) reported a case of cerebral infarction from
OHSS. Serour et al. (1998) reported a case of hepato-renal failure following
moderate OHSS. The patient was a 39-year-old woman who developed
moderate OHSS, after ovum pickup she became drowsy and never regained
full consciousness. She deteriorated quickly over a 10-day period and died
of hepato-renal failure. A retrospective review revealed a history of
hepatitis C with residual liver function impairment. Beerendonk et al.
(1998) reported four deaths in The Netherlands that occurred between 1985
and 1998.
Semba et al. (2000) reported an autopsy case of severe OHSS in a 28-year-
old Japanese female. The patient developed bilateral chest pain and progressive
dyspnea during the course of administration of human gonadotrophins. Pleural
effusion and hypouresis clinically disappeared four days after the onset of the
symptoms, but the patient died suddenly of rapid respiratory insuf¬ciency.
Autopsy revealed massive pulmonary edema, intra-alveolar hemorrhage and
pleural effusion, without any evidence of pulmonary thromboembolism.
Histopathological examination of the ovary demonstrated multiple well-
developed follicle formations consistent with OHSS. This is the ¬rst autopsy
report of a patient with severe OHSS.
We are aware of at least four cases in the UK over the last decade. All
the reported cases were following IVF but it is most certain that there
are an equal, if not larger number of cases following ovulation induction
without IVF.
94 COMPLICATIONS OF OVARIAN HYPERSTIMULATION SYNDROME




VASCULAR COMPLICATIONS

Cerebrovascular complications are by far the most serious in OHSS (Rizk, 2001,
2002) as they may result in death (Mozes et al., 1965), stroke (Rizk et al., 1990)
or amputation of a limb (Mozes et al., 1965; Mancini et al., 2001).


Incidence of Vascular Complications
The incidence of thromboembolism could not be determined with
accuracy because of the absence of registration for OHSS cases or their
complications (Delvigne and Rozenberg, 2003; Rizk and Nawar, 2004). Three
large series of OHSS studies from Belgium, Israel and Egypt reported
thromboembolic complications. In Belgium during a period of four years,
one case of cerebral thrombosis (0.8%) was documented among 128 cases of
OHSS (87% moderate and severe). In Israel, over a period of 10 years, an
incidence of 2.4% of thromboembolic complications was observed among
209 cases of severe forms of OHSS (Abramov et al., 1999a). Serour et al.
(1998) reported 10% of thromboembolic phenomena among patients with
severe OHSS. The authors studied in detail the complications of assisted
reproductive technology in 3500 IVF cycles. Ovarian hyperstimulation occurred
in its moderate form in 206 cycles (5.9%) and in its severe form in 60 cycles
(1.7%). Deep vein thrombosis occurred in four patients (0.12%) and
hemiparesis in two patients (0.06%). All cases in this series were associated
with severe OHSS.


Localization of Thromboembolic Complications
Delvigne (2004) found 68 cases of thrombosis reported in the literature.
Among these, 34.3% of the cases were arterial and 65.7% were venous.
The upper and lower body distribution was interesting. Some 83% was
localized in the upper part of the body and 17% in the lower part. Of the
upper body thromboses, 60% were venous and 40% were arterial. Of
the lower body thromboses, 81% were venous and 19% were arterial.
There were as many patients with early and late OHSS complicated by
thrombosis, and also as many singleton as multiple pregnancies complicated
by thromboses.


Internal Jugular Venous Thrombosis and OHSS
Schanzer et al. (2000) reviewed the case reports involving jugular venous
thrombosis associated with pregnancy and/or OHSS. Belaen et al. (2001)
reported a case of internal jugular vein thrombosis after ovarian stimulation
with gonadotrophins. Screening for hereditary hypercoagulability for this
patient was negative. The patient was successfully treated with low-molecular-
weight heparin and a twin pregnancy was diagnosed.
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VASCULAR COMPLICATIONS




Thromboembolic Complications without Severe OHSS
To date, several important cases of thromboembolism have been reported in
association with gonadotrophin stimulation without severe OHSS (Kligman
et al., 1995; Germond et al., 1996; Stewart et al., 1997a; Aboulghar et al., 1998;
Loret de Mola et al., 2000). Some of these cases occurred in patients with pre-
disposing factors (Kligman et al., 1995; Stewart et al., 1997) and others in the
presence of spontaneous OHSS (Todros et al., 1999). Aboulghar et al. (1998)
described two patients who developed moderate OHSS without evidence of
hemoconcentration. Both developed serious cerebrovascular thromboses
resulting in hemiparesis, and were treated with anticoagulants and recovered.
This report emphasizes the role of other factors that can result in vascular
thrombosis and illustrates that cerebrovascular accidents may complicate
moderate OHSS. Delvigne (2004) advised caution in all cases of OHSS since
thrombosis complicated about 12% of moderate OHSS cases as well as about
12% of mild OHSS cases. Furthermore, thromboses could appear as late as 20
weeks gestation, even in the absence of hemoconcentration, and in severe cases
the event occurred several weeks after OHSS (Delvigne and Rosenberg, 2003).
Stewart et al. (1997a) reported three cases of upper limb deep venous
thrombosis in association with assisted conception, the cause of which was
largely unexplained. The authors stressed that not only did these thromboses
occur in unusual sites, but that they also occurred well after the assumed peak
period of risk.
Loret de Mola et al. (2000) reported two cases of subclavian deep vein
thrombosis associated with the use of recombinant follicle-stimulating
hormone (Gonal-F) complicating mild OHSS. A case of cortical vein
thrombosis presenting as intracranial hemorrhage was described in a patient
with OHSS after IVF and embryo transfer (ET). Veno-occlusive disease of the
brain could appear as a hemorrhagic lesion on magnetic resonance imaging
(MRI), and this made the initial diagnosis of cortical vein thrombosis dif¬cult.
The patient developed deep vein thrombosis two weeks after the intracranial
event, and the diagnosis of cortical vein thrombosis was made at the time
of MRI study after the resolution of the hemorrhage. The patient actually
developed generalized thrombosis as a complication of OHSS (Shan Tang et al.,
2000). Although the initial MRI picture may be misleading, the diagnosis of
thrombosis should always be kept in mind, as it is the commonest cause of
intracranial lesions after OHSS.


Timing of Thromboses: Early and Late
Thrombosis following the development of OHSS can occur in the luteal phase
but can also occur several weeks after the development of the syndrome
(Rizk and Aboulghar, 2005). Ong et al. (1991) reported internal jugular
vein thrombosis occurring more than six weeks after ovulation, and Mills
et al. (1992) reported subclavian vein thrombosis seven weeks after egg
96 COMPLICATIONS OF OVARIAN HYPERSTIMULATION SYNDROME




Table V.1 Pathogenesis of thromboembolism in OHSS

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