A Mutation in the Follicle-Stimulating Hormone Receptor as a Cause of Familial Spontaneous Ovarian Hyperstimulation Syndrome

Università di Pisa, Pisa, Tuscany, Italy
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.31). 05/2004; 89(4):1255-8. DOI: 10.1210/jc.2003-031910
Source: PubMed

ABSTRACT Ovarian hyperstimulation syndrome (OHSS) occurs mainly after excessive stimulation of the ovaries by exogenous gonadotropins administrated in the context of in vitro fertilization procedures (iatrogenic OHSS). Recently, spontaneous and recurrent occurrence of the disease (spontaneous OHSS) was shown in two families to be caused by mutations affecting the follitropin receptor (FSHr). The two mutant FSHr (T449I, D567N) harbor aminoacid substitutions in the serpentine portion of the receptor and display abnormally high sensitivity to the pregnancy hormone hCG, thus providing a satisfactory explanation to the phenotype. In addition, mutant D567N showed also increased sensitivity to thyrotopin (TSH) and displayed increase in basal (ligand-independent) activity. In this report, we describe a new familial case of recurrent OHSS. The affected women were heterozygous for a different mutation involving codon 449, where an alanine was substituted for threonine. Similar to D567N, the T449A FSHr mutant shows an increase of its sensitivity to both hCG and TSH, together with an increase in basal activity. Together with the two previous studies, this report shows that inappropriate stimulation of the FSHr by hCG is a cause of spontaneous OHSS.

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    • "because the mutations provoke conformational changes in the receptor structure that, besides triggering modest constitutive activity, " relax " the binding specificity of the receptor, allowing the altered receptor to bind and become activated by high concentrations of CG (De Leener et al., 2006; Montanelli, Delbaere, et al., 2004; Smits et al., 2003; Vasseur et al., 2003) or TSH (De Leener et al., 2006; Montanelli, Delbaere, et al., 2004; Smits et al., 2003). As discussed in the succeeding text, in the unliganded state, the ectodomain of the FSHR exerts a putative inhibitory influence on the TMD keeping the receptor in an inactive state. "
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    ABSTRACT: Constitutively active mutants (CAMs) of gonadotropin receptors are, in general, rare conditions. Luteinizing hormone-choriogonadotropin receptor (LHCGR) CAMs provoke the dramatic phenotype of familial gonadotropin-independent isosexual male-limited precocious puberty, whereas in females, there is not yet any identified phenotype. Only one isolated follicle-stimulating hormone receptor (FSHR) CAM (Asp567Gly) has so far been detected in a single male patient, besides other FSHR weak CAMs linked to pregnancy-associated ovarian hyperstimulation syndrome or to impaired desensitization and internalization. Several animal models have been developed for studying enhanced gonadotropin action; in addition to unraveling valuable new information about the possible phenotypes of isolated FSHR and LHCGR CAMs in women, the information obtained from these mouse models has served multiple translational goals, including the development of new diagnostic and therapeutic targets as well as the prediction of phenotypes for mutations not yet identified in humans. Mutagenesis and computational studies have shed important information on the physiopathogenic mechanisms leading to constitutive activity of gonadotropin receptors; a common feature in these receptor CAMs is the release of stabilizing interhelical interactions between transmembrane domains (TMDs) 3 and 6 leading to an increase, with respect to the wild-type receptor, in the solvent accessibility at the cytosolic extension of TMDs 3, 5, and 6, which involves the highly conserved Glu/Asp-Arg-Tyr/Trp sequence. In this chapter, we summarize the structural features, functional consequences, and mechanisms that lead to constitutive activation of gonadotropin receptor CAMs and provide information on pharmacological approaches that might potentially modulate gonadotropin receptor CAM function.
    Advances in pharmacology (San Diego, Calif.) 01/2014; 70:37-80. DOI:10.1016/B978-0-12-417197-8.00002-X
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    • "Asp567Asn Normal Smits et al. [11] Dieterich et al. [18] Asp567Asn Normal Di Carlo et al. [19] Thr449Ala Normal Montanelli et al. [14] Chae et al. [20] Iso554Thr Normal De Leener et al. [6] Panagiotopoulou et al. (present paper) Iso554Thr Normal Vasseur et al. [13] Thr449Ile Normal Vasseur et al. [13] Suzuki et al. [21] Asp567Gly Normal Montanelli et al. [12] Cepni et al. [22] Ser128Tyr Normal De Leener et al. [15] Type II Gestational trophoblastic disease Hooper et al. [23] Not tested High hCG levels, complete mole Moneta et al. [24] Not tested High hCG levels, complete mole Cappa et al. [25] Not tested High hCG levels, complete mole Ludwig et al. [26] Not tested High hCG levels, partial mole Arora et al. [27] No tested High hCG levels, complete mole Strafford et al. [28] Not tested High hCG levels, complete mole Rachad et al. [29] Not tested High hCG levels, invasive mole Zhou et al. [30] Not tested High hCG levels, complete mole Multiple pregnancy Leis et al. [31] Not tested High hCG levels, twin gestation Suzuki et al. [21] No mutation High hCG levels, twin gestation Preeclampsia Saisto et al. [32] No mutation High hCG levels Idiopathic Rosen et al. [33] Not tested High hCG levels Haimov-Kochman et al. [34] No mutation High hCG levels Olesen et al. [35] No mutation High hCG levels Michaelson-Cohen et al. [36] No mutation High hCG levels O'Brien et al. [37] Not tested High hCG levels Type III Rotmensch et al. [38] Not tested High TSH levels Chen et al. [39] Not tested High TSH levels Nappi et al. [40] No mutation High TSH levels Cardoso et al. [41] Not tested High TSH levels Taher et al. [42] No mutation High TSH levels Mousavi et al. [43] Not tested High TSH levels Edwards-Silva et al. [44] "
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    ABSTRACT: Spontaneous ovarian hyperstimulation syndrome is an extremely rare condition that occurs in the absence of ovarian hyperstimulation treatment. It can lead to significant morbidity and mortality, and therefore early diagnosis and supportive treatment are essential. We report an affected mother and her daughter with a previously reported heterozygous activating mutation in the FSHR gene. We performed a literature review with particular regard to pathogenesis, with a view to suggesting a pathophysiological classification system and a diagnostic algorithm to assist in the management of this rare condition.
    European journal of obstetrics, gynecology, and reproductive biology 04/2013; 169(2). DOI:10.1016/j.ejogrb.2013.03.004 · 1.63 Impact Factor
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    • "In human medicine, thyroid disorders have been associated with ovarian hyperstimulation syndrome (OHSS) (Vasseur et al., 2003; Montanelli et al., 2004; Shu et al., 2011) and with polycystic ovary syndrome (PCOS) (Jung et al., 2011). Both hypothyroidism (Shu et al., 2011) and hyperthyroidism (Jung et al., 2011) have been associated with ovarian cysts in pre-menopausal women. "
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    ABSTRACT: Thyroid activity affects the functionality of the reproductive axis and thyroid dysfunction has been associated with ovarian hyperstimulation syndrome and polycystic ovarian syndrome, in human medicine. This study investigates serum17- estradiol, progesterone, thyrotropic and thyroid hormone levels, in cyclic dairy cows on heat (Group H) and in dairy cows with ovarian follicular cysts (Group FC). Both 17- estradiol and progesterone serum concentrations were statistically higher in cystic than in cyclic cows (estradiol: 8.51±1.91 vs 6.32±1pg/mL) (progesterone: 0.49±0.17 vs 0.13±0.03ng/mL), whereas TSH and fT4 serum concentrations were statistically lower in cows with cystic ovarian follicles (COF), compared to cyclic ones (TSH: 2.48±1.31 vs 3.56±1.03ng/mL) (fT4: 5.86±1.69 vs 8.63±1.08). fT3 serum levels were similar, in both cystic and cyclic subjects (2.94±0.65 vs 3.02±0.9, respectively). Based on these results it was decided to examine the function of the thyrothropic axis of dairy cows in a similar manner to that conducted on humans. If severe hypothyroidism should be found, a hormone replacement therapy could be attempted in cystic cows refractory to "ordinary" therapies.
    Animal reproduction science 03/2013; 138(3-4). DOI:10.1016/j.anireprosci.2013.02.024 · 1.58 Impact Factor
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