1 Clinique de Fertilité and 2 Service de Génétique médicale, Hôpital Erasme, Brussels, 3 Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium, 4 Department of Obstetrics, Gynecology and Reproductive Sciences and 5 Reproductive Biology Research Unit, College of Medicine, University of Saskatchewan, Saskatoon, Canada
6 To whom correspondence should be addressed at Clinique de Fertilité, Hôpital Erasme, 808 route de Lennik, 1070 Brussels, Belgium. e-mail: adelbaer{at}ulb.ac.be
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() |
---|
Key words: FSH receptor/OHSS/physiopathology
![]() |
![]() ![]() ![]() ![]() |
---|
hCG is thought to play a crucial role in the development of the syndrome: severe forms are indeed restricted to cycles with exogenous hCG (to induce ovulation or as luteal phase support) or with endogenous pregnancy-derived hCG (Delbaere et al., 1997b).
Spontaneous forms of OHSS are very rare and always reported during pregnancy. Several cases have been observed during multiple pregnancies (Check et al., 2000) or hydatidiform moles known to be associated with abnormally high values of hCG (Ludwig et al., 1998
). Other cases were associated with hypothyroidism and it was suggested that the high levels of thyroid-stimulating hormone (TSH) could stimulate the ovaries (Nappi et al., 1998
). A series of cases were recurrent with the development of the syndrome reported in two to six consecutive pregnancies (Zalel et al., 1995
; Olatunbosun et al., 1996
; Di Carlo et al., 1997
; Edi-Osagie and Hopkins, 1997
). Spontaneous forms of OHSS were generally reported to develop between 8 and 14 weeks amenorrhoea, differing from iatrogenic OHSS usually starting between 3 and 5 weeks amenorrhoea.
We recently identified a mutation in the FSH receptor gene in a patient presenting spontaneous OHSS during each of her four pregnancies (Smits et al., 2003a). The mutation consisted of a substitution of an adenine for a guanine at the first base of codon 567 in exon 10 of the follitropin receptor gene, resulting in the replacement of an aspartic acid with an asparagine. When tested in vitro, the functional response of the mutant receptor displayed an enhanced basal activity and an increased sensitivity to hCG. A distinct mutation in the FSH receptor gene was concomitantly reported in a patient who developed OHSS during all of her four pregnancies that went beyond 6 weeks of gestation (Vasseur et al., 2003
). The mutation was also found in the DNA of two patients sisters who similarly presented spontaneous OHSS during their pregnancies but not in that of a third unaffected sister. The mutation consisted of a substitution of a thymidine for a cytosine in exon 10 of the follitropin receptor gene resulting in the replacement of a threonine by an isoleucine at position 449 of the follitropin receptor protein. In vitro characterization of the mutated receptor also revealed an increased sensitivity to hCG.
In these reported cases, the abnormal functionality of both mutant FSH receptors in vitro provides a straightforward explanation for their implication in the OHSS development in vivo. During pregnancy, the expression of FSH receptor decreases drastically in the corpus luteum, but remains constant in granulosa cells of developing follicles (Simoni et al., 1997). These receptors are usually not or only very weakly stimulated during pregnancy, as pituitary gonadotrophins fall to very low or undetectable levels in serum. The mutated FSH receptor expressed in the developing follicles may be hyperstimulated by the pregnancy-derived hCG. Accordingly, the follicles may start growing, enlarge and finally acquire LH receptors on granulosa cells which may also be stimulated by hCG, inducing follicular luteinization together with the secretion of vasoactive molecules responsible for the development of the syndrome.
The interaction between hCG and the FSH receptor could be an essential prerequisite in the development of spontaneous OHSS and could explain why symptoms in spontaneous cases of OHSS appear later than in iatrogenic OHSS in which follicular recruitment and enlargement occur during the ovarian stimulation with exogenous FSH (Figure 1). It is likely that the stimulation of the mutated FSH receptor occurs at a threshold level of hCG which could vary according to the type of mutation. HCG usually peaks between 8 and 10 weeks of pregnancy and declines thereafter. Consequently, the initiation of follicular growth by pregnancy-derived hCG could start between 6 and 10 weeks amenorrhoea. Assuming that these follicles have the same development rate as during a normal or a stimulated cycle (2 weeks before starting luteinization), the development of the OHSS symptoms is expected to occur in parallel to the massive follicular luteinization, thus between 8 and 12 weeks amenorrhoea (Figure 1). This corroborates most clinical observations as the symptomatology of spontaneous cases of OHSS usually develops as of 8 weeks amenorrhoea culminating at the end of the first trimester of pregnancy.
|
Glycoprotein hormones (hCG, LH, FSH and TSH) are heterodimers consisting of a common -subunit and a receptor-specific
-subunit. The glycoprotein hormone receptors are G protein-coupled receptors characterized by a large extracellular domain responsible for the specific recognition and binding of the hormones. HCG and LH, displaying very high sequence similarity between their
-subunits, bind to the same LH/CG receptor, whereas TSH and FSH bind to TSH receptor and FSH receptor respectively. The above-described FSH receptor mutations both induce a reduction of ligand specificity allowing the activation of the mutated receptor by hCG. Similarly, a mutation in the TSH receptor increasing the affinity for hCG has also been shown to be responsible for familial gestational hyperthyroidism (Rodien et al., 1998
).
Spontaneous cases of OHSS are probably not all related to a mutation in the FSH receptor gene. Other clinical conditions could induce the development of the syndrome: a similar mechanism of follicular recruitment, enlargement and luteinization might happen in spontaneous cases of OHSS associated with high levels of hCG. It has been shown recently that hCG was able to stimulate TSH and FSH receptors in vitro in conditions that mimic high ligand concentrations (Schubert et al., 2003; Smits et al., 2003b
; Vischer et al., 2003
). In vivo, the activation of the TSH receptor by hCG has been demonstrated in cases of gestational hyperthyroidism (Glinoer et al., 1997
). Very high concentrations of hCG as found in molar or multiple pregnancies could therefore also stimulate FSH receptors expressed in developing follicles.
Altogether, these observations support the development of OHSS, whether iatrogenic or spontaneous, as a consequence of multiple corpora lutea formation associated with active angiogenesis and increased capillary permeability. Luteinization of enlarged superstimulated ovaries may induce the massive release of vasoactive mediators such as vascular endothelial growth factor (McClure et al., 1994), angiotensin II (Delbaere et al., 1994
, 1997a) and various interleukins (Abramov et al., 1996
), exacerbating local inflammatory-like reactions accompanying angiogenesis during corpora lutea formation. As the release of vasoactive molecules reaches a threshold, physiological control mechanisms can be overstretched, leading to the development of the symptoms of OHSS.
It is noteworthy that the kinetics of the symptoms are closely related to the lifespan of the corpus luteum. During iatrogenic OHSS, in the absence of pregnancy, symptoms will resolve spontaneously with the onset of the menses; in the presence of pregnancy, symptoms usually start to improve after the sixth week of pregnancy, before the hCG peak. Accordingly, it has been demonstrated that the activity of the corpus luteum diminishes from the fifth week of pregnancy despite increasing hCG levels (Tulchinsky and Hobel, 1973). During spontaneous OHSS, the initial corpus luteum related to the pregnancy is not responsible for the development of the OHSS symptomatology. The formation of secondary multiple corpora lutea, or at least of a critical mass of luteinized granulosa cells, could induce a massive release of vasoactive mediators leading to the development of the syndrome.
The role of estradiol (E2) levels has been recently debated in the prediction of OHSS (Orvieto, 2003; Aboulghar, 2003
). While a threshold level of E2 has been used in several studies to withhold hCG administration during ovarian stimulation for IVF cycles (Delvigne and Rozenberg, 2002
; Aboulghar and Mansour, 2003
), its reliability has been questioned especially since OHSS also occurs in patients who conceive spontaneously and whose pre-ovulatory serum E2 levels are far less than those encountered after pharmacological ovarian stimulation (Orvieto, 2003
). These two pieces of apparently conflicting clinical evidence can be reconciled considering that in iatrogenic OHSS, high pre-ovulatory E2 levels are the expression of multiple follicular recruitment by exogenous gonadotrophin administration, while in spontaneous OHSS the follicular recruitment occurs later under the action of pregnancy-derived hCG, leading in all cases to massive luteinization of enlarged stimulated ovaries, the first step in the cascade of events leading to the development of OHSS.
In conclusion, these recent findings provide for the first time the molecular basis for the physiopathology of spontaneous OHSS and open new perspectives to understand the development of iatrogenic OHSS. While a mutation in the FSH receptor gene should be sought in the presence of recurrent or familial spontaneous OHSS, it would be interesting to ascertain whether polymorphisms of glycoprotein hormone or receptor genes could constitute risk factors in the development of iatrogenic OHSS.
![]() |
References |
---|
![]() ![]() ![]() ![]() |
---|
Aboulghar MA and Mansour RT (2003) Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures. Hum Reprod Update 9,275289.
Abramov Y, Schenker JG, Lewin A, Friedler S, Nisman B and Barak V (1996) Plasma inflammatory cytokines correlate to the ovarian hyperstimulation syndrome. Hum Reprod 11,13811386.
Check JH, Choe JK and Nazari A (2000) Hyperreactio luteinalis despite the absence of a corpus luteum and suppressed follicle stimulating concentrations in a triplet pregnancy. Hum Reprod 15,10431045.
Delbaere A, Bergmann PJM, Gervy-Decoster C, Staroukine M and Englert Y (1994) Angiotensin II immunoreactivity is elevated in ascites during severe ovarian hyperstimulation syndrome: implications for pathophysiology and clinical management. Fertil Steril 62,731737.[ISI][Medline]
Delbaere A, Bergmann PJM, Gervy-Decoster C, Camus M, de Maertelaer V and Englert Y (1997a) Prorenin and active renin concentrations in plasma and ascites during severe ovarian hyperstimulation syndrome. Hum Reprod 12,236240.[Abstract]
Delbaere A, Bergmann PJM, Gervy-Decoster C, Deschodt-Lanckman M, de Maertelaer V, Staroukine M, Camus M and Englert Y (1997b) Increased angiotensin II in ascites during severe ovarian hyperstimulation syndrome: role of early pregnancy and ovarian gonadotropin stimulation. Fertil Steril 67,10381045.[CrossRef][ISI][Medline]
Delvigne A and Rozenberg S (2002) Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update 8,559577.
DiCarlo C, Bruno PA, Cirillo D, Morgera R, Pellicano M and Nappi C (1997) Increased concentrations of renin, aldosterone and Ca125 in a case of spontaneous, recurrent, familial, severe ovarian hyperstimulation syndrome. Hum Reprod 12,21152117.[Abstract]
DiZerega G and Hodgen G (1979) Pregnancy-associated ovarian refractoriness to gonadotropin: a myth. Am J Obstet Gynecol 134,819822.[ISI][Medline]
Elchalal U and Schenker JG (1997) The pathophysiology of ovarian hyperstimulation syndromeviews and ideas. Hum Reprod 12,11291137.[CrossRef][ISI][Medline]
Edi-Osagie ECO and Hopkins RE (1997) Recurrent idiopathic ovarian hyperstimulation syndrome in pregnancy. Br J Obstet Gynaecol 104,952954.[ISI][Medline]
Glinoer D (1997) The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 18,404433.
Hollemaert S, Wautrecht J-C, Capel P, Abramowicz MJ, Englert Y and Delbaere A (1996) Thrombosis associated with ovarian hyperstimulation syndrome in a carrier of the factor V Leiden mutation. Thromb Haemost 76,275276.
Ludwig M, Gembruch U, Bauer O and Diedrich K (1998) Ovarian hyperstimulation syndrome (OHSS) in a spontaneous pregnancy with fetal and placental triploidy: information about the general pathophysiology of OHSS. Hum Reprod 13,20822087.[Abstract]
McClure N, Healy DL, Rogers PAW, Sullivan J, Beaton L, Haning Jr, RV, Connolly DT and Robertson DM (1994) Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome. Lancet 344, 235236.[ISI][Medline]
Nappi RG, Di Nero E, DAries AP and Nappi L (1998) Natural pregnancy in hypothyroid woman complicated by spontaneous ovarian hyperstimulation syndrome. Am j Obstet Gynecol 178,610611.[ISI][Medline]
Navot D, Bergh PA and Laufer N (1992) Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 58,249261.[ISI][Medline]
Olatunbosun OA, Gilliland B, Brydon LA, Chizen DR and Pierson RA (1996) Spontaneous ovarian hyperstimulation syndrome in four consecutive pregnancies. Clin Exp Obstet Gynecol 23,127132.[Medline]
Orvieto R (2003) Prediction of ovarian hyperstimulation syndrome. Challenging the estradiol mythos. Hum Reprod 18,665667.
Rodien P, Bremont C, Sanson ML, Parma J, Van Sande J, Costagliola S, Luton JP, Vassart G and Duprez L (1998) Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 339,18231826.
Schubert RL, Narayan P and Puett D (2003) Specificity of cognate ligand-receptor interactions: fusion proteins of human chorionic gonadotropin and the heptahelical receptors for human luteinizing hormone, thyroid-stimulating hormone, and follicle-stimulating hormone. Endocrinology 144,129137.
Simoni M, Gromoll J and Nieschlag E (1997) The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology. Endocr Rev 18,739773.
Smits G, Olatunbosun OA, Delbaere A, Pierson RA, Vassart G and Costagliola S (2003a) Spontaneous ovarian hyperstimulation syndrome caused by a mutant follitropin receptor. N Engl J Med 349,760766.
Smits G, Campillo M, Govaerts C, Janssens V, Richter C, Vassart G, Pardo L and Costagliola S (2003b) Glycoprotein hormone receptors: determinants in leucine-rich repeats responsible for ligand specificity. EMBO J 22,26922703.
Tulchinsky D and Hobel CJ (1973) Plasma human chorionic gonadotropin, estrone, estradiol, progesterone, and 17-hydroxyprogesterone in human pregnancy. Am J Obstet Gynecol 117,884893.[ISI][Medline]
Vasseur C, Rodien P, Beau I, Desroches A, Gérard C, de Poncheville L, Chaplot S, Savagner F, Croué A, Mathieu E et al (2003) A chorionic gonadotropin-sensitive mutation in the follicle-stimulationg hormone receptor as a cause of a familial gestational spontaneous ovarian hyperstimulation syndrome. N Engl J Med 349,753759.
Vischer HF, Granneman JC, Noordam MJ, Mosselman S and Bogerd J (2003) Ligand selectivity of gonadotropin receptors. Role of the beta-strands of extracellular leucine-rich repeats 3 and 6 of the human luteinizing hormone receptor. J Biol Chem 278,1550515513.
White CA and Bradbury JT (1965) Ovarian theca lutein cysts. Experimental formation in women prior to repeat cesarean section. Am J Obstet Gynecol 92,973980.[ISI]
Zalel Y, Orvieto R, Ben-Rafael Z, Homburg R, Fisher O and Insler V (1995) Recurrent spontaneous ovarian hyperstimulation syndrome associated with polycystic ovary syndrome. Gynecol Endocrinol 9,313315.[ISI][Medline]
Submitted on August 28, 2003; accepted on November 11, 2003.