LINEBURG


<< . .

 11
( 30)



. . >>




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. Proceedings of the 34th ASRM Annual Postgraduate Program,
Middle East Fertility Society Precongress Course. ASRM, 57th Annual Meeting,
Orlando, FL, October 2001, pp. 23À46.
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.
Proceedings of the 35th ASRM Annual Postgraduate Program, Middle East
Fertility Society Precongress Course. ASRM, 58th Annual Meeting, Seattle, WA,
October 2002, pp. 65À102.
Rizk B & Abdalla H (2003). Pathogenesis of endometriosis. In (Rizk B, Abdalla H, Eds),
Endometriosis, 2nd edn. Oxford: Health Press, Chapter 1, pp. 9À23.
Rizk B & Aboulghar M (1991). Modern management of ovarian hyperstimulation
syndrome. Hum Reprod 6:1082À7.
Rizk B & Aboulghar MA (1999). Classi¬cation, pathophysiology and management of
ovarian hyperstimulation syndrome. In (Brinsden P, Ed.), A Textbook of In-Vitro
Fertilization and Assisted Reproduction, 2nd edn. London: Parthenon Publishing,
Chapter 9, pp. 131À55.
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, 3rd edn. 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:
Cambridge University Press, Chapter 8, pp. 146À66.
Rizk B & Abdalla H (2006). Ovulatory dysfunction and its management. In (Rizk B &
Abdullah M, Eds), Infertility and Assisted Reproductive Technology. Oxford: Health
Press, Chapter 1, pp. 87À9.
Rizk B & Smitz J (1992). Ovarian hyperstimulation syndrome after superovulation for
IVF and related procedures. Hum Reprod 7:320À7.
Rizk B, Meagher S & Fisher AM (1990). Ovarian hyperstimulation syndrome and
cerebrovascular accidents. Hum Reprod 5:697À8.
Rizk B, Aboulghar MA, Mansour RT et al. (1991). Severe ovarian hyperstimulation
syndrome: analytical study of twenty-one cases. Proceedings of the VII World Congress
on In-Vitro Fertilization and Assisted Procreations, Paris. Hum Reprod 8:368À9.
Rizk B, Aboulghar MA, Smitz J & Ron-El R (1997). The role of vascular endothelial
growth factor and interleukins in the pathogenesis of severe ovarian hyperstimulation
syndrome. Hum Reprod Update 3:255À66.
Roberts JE, Spandorfer S, Fasouliotis SJ et al. (2005). Spontaneous ovarian hyperstimula-
tion caused by a follicle-stimulating hormone-secreting pituitary adenoma. Fertil
Steril 83:208À10.
Rosenberg ME, Mckinzie JK, Mckenzie LM et al. (1994). Increased ascitic ¬‚uid prorenin in
the ovarian hyperstimulation syndrome. Am J Kidney Dis 23:427À9.
Sahin Y, Kontas O, Muderris II et al. (1997). Effects of angiotensin converting enzyme
inhibitor cilasaprin and angiotensin II antagonist saralasin in ovarian hyperstimula-
tion syndrome in the rabbit. Gynecol Endocrinol 11:231À6.
Schenker JG (1999). Clinical aspects of ovarian hyperstimulation syndrome. Eur J Gynecol
Reprod Biol 85:10À3.
Schenker JG & Polishuk WZ (1976). The role of prostaglandins in ovarian hyperstimula-
tion syndrome. Obstet Gynecol Surv 31:74À8.
Schenker JG & Weinstein D (1978). Ovarian hyperstimulation syndrome: a current survey.
Fertil Steril 30:255À68.
Senger DR, Galli SJ, Dvorak AM et al. (1983). Tumor cells secrete a vascular permeability
factor that promotes accumulation of ascites ¬‚uid. Science 219:983À5.
78 PATHOPHYSIOLOGY OF OVARIAN HYPERSTIMULATION SYNDROME




Shimon J, Rubinek T, Bar-Hava I et al. (2001). Ovarian hyperstimulation without elevated
serum estradiol associated with pure follicle-stimulating hormone-secreting pituitary
adenoma. J Clin Endocrinol Metab 86:3635À40.
Shweiki D, Itin A, Neufeld G et al. (1993). Patterns of expression on vascular endothelial
growth factor (VEGF) receptors in mice suggest a role in hormonally regulated
angiogenesis. J Clin Invest 91:2235À43.
Smitz J, Camus M, Devroey P et al. (1990). Incidence of severe ovarian hyperstimulation
syndrome after GnRH-agonistÀHMG treatment in super ovulation in vitro
fertilization. Hum Repord 5:933À7.
Snyder PJ (1985). Gonadotroph cell adenomas of the pituitary. Endocrinol Rev 6:552À63.
Snyder PJ (1987). Gonadotroph cell pituitary adenomas. Endocrinol Metab Clin North Am
16:755À64.
Soker S, Takashima S, Miao H et al. (1998). Neuropilin-1 is expressed by endothelial
and tumor cells as an isoforms speci¬c receptor for vascular endothelial growth
factor. Growth Factors 92:735À45.
Tischer E, Gospodarowicz D, Mitchell R et al. (1989). Vascular endothelial growth factor:
a new member of the platelet-derived growth factor gene family. Biochem Biophys Res
Commun 165:1198À206.
Tollan A, Holst N, Forsdahl F et al. (1990). Transcapillary ¬‚uid dynamics during ovarian
stimulation for in-vitro fertilization. Am J Obstet Gynecol 162:554À6.
Teruel MJ, Carbonell LF, Llanos MC et al. (2002). Hemodynamic state and the role of
angiotensin II in ovarian hyperstimulation syndrome in the rabbit. Fertil Steril
77:1256À60.
Teruel MJ, Carbonell LF, Teruel MG et al. (2001). Effect of angiotensin-converting enzyme
inhibitor on renal function in ovarian hyperstimulation syndrome in the rabbit. Fertil
Steril 76:1232À7.
Todorow S, Schricker ST, Siebzinruebl ER et al. (1993). Von Willebrand factor: an
endothelial marker to monitor in vitro fertilization patients with ovarian hyper-
stimulation syndrome. Hum Reprod 8:2039À49.
Valimaki MJ, Tiitinen A, Alfthan H et al. (1999). Ovarian hyperstimulation caused
by gonadotroph adenoma secreting follicle-stimulating hormone in a 28 year old
woman. J Clin Endocrinol Metab 84:4204À8.
Van Beaumont W (1872). Evaluation of hemoconcentration from hematocrit measure-
ments. J Appl Physiol 5:712À3.
Van der Meeren A, Squiban C, Guormelon P et al. (1991). Differential regulation by IL-4
and IL-10 of radiation induced IL-6 and IL-8 production and ICAM-1 expression by
human endothelial cells. Cytokine 11:831À8.
Wang LJ & Norman RJ (1992). Concentrations of immunoreactive interleukin-1 and
interleukin-2 in human preovulatory follicular ¬‚uid. Hum Reprod 7:147À50.
Wang LJ, Robertson S, Seamark RF et al. (1991). Lymphokines, including interleukin-2
alter gonadotrophin-stimulated progesterone production and proliferationof human
granulosa-luteal cells in vitro. J Clin Endocrinol Metab 72:824À31.
Wang LJ, Pascoe V, Petrucco OM et al. (1992). Distribution of leukocyte subpopulations
in the human corpus luteum. Hum Reprod 7:197À202.
Wang TH, Horng SG, Chang CL et al. (2002). Human chorionic gonadotropin-induced
ovarian hyperstimulation syndrome is associated with up-regulation of vascular
endothelial growth factor. J Clin Endocrinol Metab 87:3300À8.
Yan Z, Weich HA, Bernart W et al. (1993). Vascular endothelial growth factor (VEGF)
messenger ribonucleic acid (mRNA) expression in luteinized human granulosa cells
in-vitro. J Clin Endocrinol Metab 77:1723À5.
Yarali H, Fleige-Zahradka BG, Yuen BH et al. (1993). The ascites in the ovarian
hyperstimulation syndrome does not originate from the ovary. Fertil Steril 59:
657À61.
IV

GENETICS OF OVARIAN
HYPERSTIMULATION SYNDROME


FOLLICLE STIMULATING HORMONE: STRUCTURE,
FUNCTION AND RECEPTOR

Follicle stimulating hormone (FSH) is the central hormone of human
reproduction necessary for gonadal development and maturation at puberty
and for gamete production during the fertile phase of life (Simoni et al., 1997;
Rizk and Abdalla, 2006). Together with luteinizing hormone (LH), FSH is
produced and secreted by the pituitary gland as a highly heterogenous
glycoprotein. FSH, LH and hCG consist of a common alpha subunit and a
receptor speci¬c beta subunit (Figures IV.1, IV.2 and IV.3). FSH acts by binding
to speci¬c receptors localized speci¬cally in the gonads.
The FSH receptor is a glycoprotein belonging to the family of G-protein-
coupled receptors. Complex transmembrane proteins are characterized by
seven hydrophobic helices inserted in the plasmalemma and by intracellular
and extracellular domains, depending on the type of the ligand (Figure IV.4).
The large extracellular domain of the glycoprotein hormone receptors is a
unique feature within the G-protein-coupled receptor family. The intracellular
portion of the FSH receptor is coupled to a Gs protein, and upon receptor
activation by the hormonal interaction with the extracellular domain, initiates
a cascade of events that ¬nally leads to the speci¬c biologic effects of the
gonadotrophin (Figure IV.5). The intramolecular mechanisms involved in the
transduction of the activation signal from the binding step to the activation of
the G protein have been the subject of intense investigations (Montanelli
et al., 2004a) whereas in most rhodopsin-like GPCRs, there is evidence for
a direct interaction between agonists and serpentine domains. Following
receptor activation by the ligand, the activated Gas subunit (GTP-bound)
stimulates the effector enzyme adenylyl cyclase, and the generation of the
cyclic AMP (cAMP) from ATP. The cAMP then activates protein kinase A
(A-kinase), triggering a phosphorylation (P) cascade and activating intracel-
lular proteins (Figure IV.5). The models for the activation of gonadotrophin
receptors suggest that binding of the hormones to the receptors would
promote a conformational change in their ectodomains, transforming them
into full agonist of the serpentine domain (Vlaeminck-Guillem et al., 2002;
Montanelli et al., 2004a).




79
80 GENETICS OF OVARIAN HYPERSTIMULATION SYNDROME




Fig. IV.1: Schematic representation of the primary structure of a- and b-subunits of the
gonadotrophin family
Reproduced with permission from Olijve et al. (1996). Mol Hum Reprod 2:371À82



FSH RECEPTOR GENE

The chromosomal mapping of the FSH receptor gene has been performed by
¬‚uorescence in situ hybridization using cDNA or genomic probes and by
linkage analysis (Rousseau-Merck et al., 1993; Gromoll et al., 1994). The FSH
receptor gene is located at chromosome 2p21 in the human (Simoni et al.,
1997; Themmen and Huhtaniemi, 2000; Simoni et al., 2002). The LH receptor
gene can be mapped to the same chromosomal location whereas the human
TSH receptor is located on chromosome 14 q31. The FSH receptor gene is a
single-copy gene and spans a region of 54 kbp in the human as determined by
restriction analysis of genomic clones and size determination of PCR probes.
It consists of 10 exons and 9 introns (Simoni et al., 1997).
81
FSH RECEPTOR GENE




Fig. IV.2: Model of a fully glycosylated and sialylated human FSH molecule
Reproduced with permission from Edwards RG, Risquez F, Eds (2003). Modern Assisted
Conception. Cambridge, UK. Reproductive Biomedicine Online: Reproductive Health Care
Ltd, p. 66




Fig. IV.3: The sequence of the common human a-subunit (hFSHa; upper panel and
human FSHb (lower panel)
Reproduced with permission from Edwards RG, Risquez F, Eds (2003). Modern Assisted
Conception. Reproductive Biomedicine Online: Reproductive Health Care Ltd, p. 66
82 GENETICS OF OVARIAN HYPERSTIMULATION SYNDROME




Fig. IV.4: FSH receptor
Reproduced with permission from Simoni et al. (1997). Endocr Rev. 18:739À73




Fig. IV.5: Attachment to FSH receptor and signal transduction mediated by the Gas
protein pathway in response to a gonadotrophic stimulus (ligand)
Reproduced with permission from Edwards RG, Risquez F, Eds (2003). Modern Assisted
Conception. Cambridge, UK. Reproductive Biomedicine Online: Reproductive Healthcare Ltd,
p. 70



OVARIAN RESPONSE AND FSH RECEPTOR

FSH plays a central role in oogenesis. It triggers the maturation of follicles,
proliferation of granulosa cells and aromatase enzyme induction (Rizk and
Abdalla, 2006). Its role is pivotal in the recruitment of the dominant follicle.
FSH action is mediated by the FSH receptor (Figure IV.4) and, therefore,
screening for mutations in the FSH receptor has been pursued in the search for
causes of infertility (Aittomaki et al., 1995; Whithney et al., 1995; Gromoll
et al., 1996).
83
NATURALLY OCCURRING FSH RECEPTOR MUTATIONS




De Castro et al. (2003) analyzed the clinical outcome of 102 controlled
ovarian hyperstimulation cycles and the role of Ser680Asn in recombinant FSH.
Although the results suggest Ser/Ser patients have a lower response to
recombinant FSH during controlled ovarian stimulation cycles and increased
risk of cycle cancellation, the presence of Asn/Asn homozygotes among poor
responders and among patients whose cycles were cancelled indicates that the
Ser680 allele alone is not suf¬cient to cause a lower response to recombinant
FSH. Furthermore, variables of ovulation induction were similar among
genotypes, suggesting that other factors such as age, ovarian reserve or other
genes may contribute to the oucome (De Castro et al., 2003).
Serum FSH levels are among the best predictors of ovarian response.
A signi¬cant variability from cycle to cycle in the same patient is observed. The
distribution of FSH isoforms and the interference of circulating FSH inhibitors
or FSH antibodies also play a role. Ovarian response to FSH stimulation
depends on the FSH receptor genotype (Perez Mayorga et al., 2000). Two
nonsynonymous polymorphisms have been described in exon 10 of the
transmembrane region of the FSH receptor (Simoni et al., 2002). The ¬rst one
is A919G (Thr307Ala), located just before the beginning of the ¬rst
transmembrane helix and the second polymorphism is A2039G (Asn680Ser),
located intracellularly at the end of the C permanent tail of the receptor. In
Caucasian populations, four haplotypes have been described by Simoni et al.
(2002). The common haplotypes are T307N680 and A307S680 (60% and 40%,
respectively). The rare haplotypes are A307N680 T307S680 (approximately 1%
each). The presence of a serine in position 680 is associated with high basal
levels of FSH on day 2 to 4 of the menstrual cycle and higher requirements of
exogenous FSH for ovarian stimulation (Perez Mayorga et al., 2000; Sudo et al.,
2002). This means that an FSH receptor with a serine in position 680 is less
ef¬cient than an FSH receptor with an asparagine in position 680 (Perez
Mayorga et al., 2000; Sudo et al., 2002). DeCastro et al. (2003) have
demonstrated an association between the presence of serine in position 680 to
poor responses to gonadotrophin therapy in IVF patients. DeCastro et al.
(2003) suggested that the S680 allele was associated with a diminished sensitivity
to FSH. However, Laven et al. (2003) could not establish altered ovarian
sensitivity to exongenous FSH during ovulation induction in clomiphene-
resistant normo-gonadotrophic anovulatory patients. The in-vivo association
of S680 with higher levels of basal FSH on day 2 to 4 of the menstrual cycle
has not yet been explained in molecular terms (Perez Mayorga et al., 2000;
Sudo et al., 2002; Simoni et al., 2002; Daelemans et al., 2004).


NATURALLY OCCURRING FSH RECEPTOR MUTATIONS

After two decades of investigations, the FSH receptor cDNA was ¬nally cloned
in 1990 (Sprengel et al., 1990). The ¬rst mutations were described with a major
impact on the reproductive phenotype (Aittomaki et al., 1995; Gromoll et al.,
1996). The new information emerging from the naturally occurring mutations
84 GENETICS OF OVARIAN HYPERSTIMULATION SYNDROME




and the molecular work provides insights into FSH physiology (Gromoll et al.,
1996; Simoni et al., 1997).


FSH RECEPTOR MUTATIONS AND OHSS

The association between FSH receptor mutations and OHSS (Figure IV.6) has
opened new horizons in our understanding of the pathophysiology of this
syndrome (Kaiser, 2003; Rizk and Aboulghar, 2005). Recently, three naturally
occurring mutations in the serpentine region of the FSH receptor (FSHr)


Fig. IV.6: Pathogenesis of familial gestational spontaneous OHSS
Reproduced with permission from Kaiser, B (2003). N Engl J Med 349:729À32
85
FSH RECEPTOR MUTATIONS AND OHSS




(D567N and T449I/A) have been identi¬ed in three families with spontaneous
ovarian hyperstimulation syndrome. All mutant receptors displayed abnormally
high sensitivity to human chorionic gonadotrophin, and, in addition, D567N
and T449A displayed a concomitant increase in sensitivity to TSH and
detectable constitutive activity (Vasseur et al., 2003; Smits et al., 2003;
Montanelli et al., 2004a, b). Up until that point in time, few mutations in the
FSH receptor (Themmen and Huhtaniemi, 2000), and only one resulting in a
gain of function (Gromoll et al., 1996), have been reported. These three recently
published mutations broaden the speci¬city of the FSH receptor so that it
responds to another ligand, chorionic gonadotrophin (Figure IV.6).
Vasseur et al. (2003) identi¬ed a chorionic-gonadotrophin-sensitive
mutation in the FSH receptor as a cause of familial gestational spontaneous
ovarian hyperstimulation syndrome. The patient developed OHSS during all of
her four pregnancies that went beyond 6 weeks of gestation. The patient™s
sisters, who also had OHSS in their pregnancies, had the same mutation, but
another sister who did not develop OHSS did not have the mutation. The
mutation consisted of a substitution of thymidine for cytosine in exon 10 of the
follitropin receptor gene. This resulted in the replacement of threonine by an
isoleucine at position 449 of the follitropin protein (Figure IV.7). In-vitro
characterization of the mutated receptor showed an increased sensitivity
to hCG.
Smits et al. (2003) identi¬ed another mutation in the FSH receptor gene in
a patient with spontaneous OHSS during each of her four pregnancies. The
mutation consisted of a substitution of an adenine for a guanine at the ¬rst base
of the codon 567 in exon 10 of the follitropin receptor gene, resulting in the
replacement of an aspartic acid with asparagine (Figure IV.8). The functional
response of the mutant receptor when tested in-vitro displayed an increased
sensitivity to hCG.



Fig. IV.7: FSH receptor mutation and spontaneous OHSS. Sequence of exon 10 of the
follicle-stimulating hormone receptor in the proband; the arrow indicates the
heterozygous position at 449
Reproduced from Vasseur et al. (2003). N Engl J Med 349:753À9
86 GENETICS OF OVARIAN HYPERSTIMULATION SYNDROME




Fig. IV.8: FSH receptor mutation and spontaneous OHSS. Nucleotide sequence traces of
follicle-stimulating hormone receptor around codon 567, in a control subject and in a
patient with recurrent spontaneous ovarian hyperstimulation syndrome
Reproduced with permission from Smits et al. (2003). N Engl J Med 349:760À6




Fig. IV.9: FSH receptor mutation and spontaneous OHSS. Detection of the T449A
mutation. Panel A: Nucleotide sequence traces of exon 10 of the FSHr around codon 449
in a patient with spontaneous OHSS. Panel B: Family pedigree
Reproduced with permission from Montanelli et al. (2004). J Clin Endocrinol Metab
89:1255À8



Montanelli et al. (2004b) recently described a new familial case of recurrent
spontaneous OHSS associated with a different mutation affecting the residue
449 of the FSH receptor. The affected women were heterozygous for a different
mutation involving codon 449, where an alanine was substituted for threonine
(Figure IV.9). Similar to D567N, the T449A FSHr mutant shows an increased
sensitivity to both hCG and TSH, together with an increase in basal activity.
87
SPONTANEOUS AND IATROGENIC OHSS




How do FSH Receptor Mutations Result in OHSS?
Human chorionic gonadotropin activity is normally limited to LH receptors
expressed in the corpus luteum and assists in the maintenance of pregnancies.
The three mutations of the FSH receptor result in promiscuous stimulation by
hCG of the FSH receptors expressed on the granulosa cells of the ovarian
follicles, resulting in excessive follicular development. Kaiser (2003) hypothe-
sized that excessive follicular recruitment in association with luteinization of
the follicles mediated by LH receptors results in OHSS (Figure IV.6).


Unexpected Location for the FSH Mutations
The mutations in the FSH receptor led to reduction of ligand speci¬city,
permitting activation by hCG. It was very unexpected that the mutaions were
not in the hormone-binding ectodomain, but rather in the serpentine domain
that is responsible for the activation of signaling (Kaiser, 2003; Montanelli et al.,
2004a). The af¬nity for FSH was not affected and no direct binding of hCG
could be detected. These ¬ndings argue against changes in ligand binding.
Kaiser (2003) suggested that the mutations affect the speci¬city of ligand
recognition by allowing the low-af¬nity interaction of hCG with the
ectodomain of the FSH receptor to be suf¬cient to ˜˜¬‚ip the switch™™. This
would result in inducing an active con¬rmation of the serpentine domain and
downstream signaling (Figure IV.6). Furthermore, the mutation in the FSH
receptor reported by Smits et al. (2003) was such that the ligand speci¬city was
reduced to an even greater extent, permitting downstream signaling induction
by TSH in addition to hCG and FSH and also permitting constitutive activity in
the absence of ligand (Kaiser, 2003).

<< . .

 11
( 30)



. . >>

Copyright Design by: Sunlight webdesign