http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, Early Online: 1–3 ! 2015 Informa UK Ltd. DOI: 10.3109/09513590.2015.1037268
REVIEW ARTICLE
Spontaneous ovarian hyperstimulation syndrome – understanding the dilemma Amit Kumar Dey1, Abhishek Dubey1, Kartik Mittal2, and Sunita Kale2 Department of General Surgery and 2Department of Radiology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
Gynecol Endocrinol Downloaded from informahealthcare.com by University of Otago on 07/26/15 For personal use only.
1
Abstract
Keywords
Ovarian hyper-stimulation syndrome (OHSS) is an uncommon identity due to variable number of causes, gestation and gestational disease being more common than thyroiditis and other causes. The role of radiology and biochemical markers are of utmost importance in not only diagnosing spontaneous ovarian hyper-stimulation syndrome (sOHSS) but also ruling out other cystic ovarian diseases and to determine the underlying aetiology and course of the disease. Understanding its pathophysiology and genetics holds the key to unravel the mysteries of this condition.
Gonadotropin, ovarian hyper stimulation syndrome, spontaneous
Introduction Classically, ovarian hyper-stimulation syndrome (OHSS) is described as one of the side-effects in women who receive gonadotropins for induction of ovulation during assisted reproductive technology (ART) procedure [1]. However, of all stimulation cycles in assisted reproduction, the prevalence of severe form of OHSS is quite small, ranging from 0.5 to 5% or from 0.2 to 1%, as calculated by the World Health Organization [2]. Along with enlarged and polycystic ovary, ascites, pleural effusion, haemoconcentration, hypovolemia, renal failure, oliguria, thromboembolic episodes, adult respiratory distress syndrome and death may occur in severe OHSS [1,3]. It seems that when human chorionic gonadotropin (hCG) is administered, there is an increase in capillary permeability due to release of certain substances; although the pathogenesis has not been completely explained [4]. It is commonly reported in women with polycystic ovary syndrome, hypothyroidism, gonadotroph pituitary adenoma and pregnancy [1,5]. Spontaneous OHSS (sOHSS) has been reported to be associated with elevated hCG levels (either exogenously administered or as a result of endogenous pregnancy-derived hCG stimulation) and increased endothelial growth factor [5,6]. CA125 has also been reported to increase in spontaneous OHSS, but its measurement is not useful for arriving at a differential diagnosis [5]. Hyperreeactio luteinalis (HL) is another rare condition, mimicking sOHSS, which occurs during spontaneous pregnancy and is characterized by multicystic and bilateral enlargement of
Address for correspondence: Kartik Mittal, 3rd year MD, Department of Radiology, Seth GS Medical College and KEM Hospital, Room no. 107, Main boy’s hostel, Acharya Donde Marg, Parel, Mumbai – 400012, Maharashtra, India. Tel: +91-8080995687. E-mail: amit3kem@ gmail.com
History Received 19 January 2015 Revised 18 March 2015 Accepted 31 March 2015 Published online 20 July 2015
ovaries associated with high level of maternal serum hCG and hyperandrogenic state [5]. It is caused by high-beta hCG levels or abnormal beta hCG receptor sensitivity [7]. Since, pathogenesis of spontaneous OHSS and/or HL is not completely elucidated, it is difficult to differentiate spontaneous OHSS from HL if the onset is early in the first trimester [5].
Pathophysiology and genetics The report of Carlo et al. seemed to suggest the hypothesis of a genetic predisposition for spontaneous OHSS [7]. There are two main theories explaining the mechanism of occurrence of spontaneous OHSS viz. hyper-secretion of glycoprotein hormone and/or mutation of follicle stimulating hormone (FSH) receptor [8–10]. Spontaneous OHSS is usually reported during pregnancy. Many of them were observed during multiple pregnancies or hydatidiform moles having high-hCG concentration, while others presented with hypothyroidism in which high levels of thyroid stimulating hormone (TSH) have a suggestive role in ovarian stimulation [11]. In corpus luteum, the expression of FSH receptor decreases drastically, while in granulosa cells of developing follicles it remains constant during pregnancy. As serum FSH falls to a very low level, FSH receptors are not weakly stimulated, while hCG hyperstimulates the mutated FSH receptor expressed in developing follicles during pregnancy [11]. The follicles start growing, enlarge and finally acquire luteinising hormone (LH) receptors on granulosa cells, which may also be stimulated by hCG, inducing follicular luteinisation together with the secretion of vasoactive molecules responsible for the development of the syndrome [11]. Cohorts of follicles competent enough to achieve pre-ovulatory status within 10–14 days and which undergoes subsequent luteinisation under the action of hCG exist during pregnancy.
Gynecol Endocrinol Downloaded from informahealthcare.com by University of Otago on 07/26/15 For personal use only.
2
A. K. Dey et al.
In some of the secondarily recruited follicles, possibly premature luteinisation may occur [11]. As a result of multiple corpora lutea formation, there is association with active angiogenesis and increased capillary permeability leading to sOHSS. Massive release of vasoactive mediators exacerbating local inflammatory like reactions accompanying angiogenesis during corpora lutea formation may be induced by luteinisation of enlarged super stimulated ovaries [11]. Physiological control mechanism can be overstretched as the release of vasoactive molecules reaches a threshold, leading to the development of symptoms of OHSS [11]. Another possible underlying mechanism, though not fully understood, is hypergonadotropinemia caused by gonadotropinproducing pituitary adenoma [12]. Women in reproductive age with these FSH-producing pituitary adenomas exhibit spontaneous OHSS characterised by high-serum FSH and estradiol levels along with massive multicystic ovaries [12]. In some of the cases reported, FSH secreting pituitary adenoma associated with sOHSS has almost normal FSH level, and in few of these cases estradiol level was elevated [12]. Interestingly, enhanced bioactivity of FSH produced from FSH-producing adenoma is also reported, thereby aggravating OHSS even when within normal range [12]. However, in the report of Michaelson-Cohen et al. despite of high-hCG concentrations, there are many other factors triggering spontaneous OHSS. Some of these include variant hCG having high-biological activity; generation of other factors like vascular endothelial growth factor (VEGF) or having activity similar to VEGF sparked by hCG, elevated placental hormones such as estradiol promoting granulosa cell proliferation or granulose cell proliferation being more sensitive to stimulation of FSHr [13]. Clinical signs and symptoms In contrast to the iatrogenic OHSS which is usually reported to develop between 3 and 5 months, spontaneous OHSS generally starts from 8 to 14 weeks of amenorrhea [11]. However, activity of corpus luteum diminishes from 5th week of pregnancy in spite of increasing hCG level [11]. As in the report of Delbaere et al. during sOHSS, the ‘‘initial’’ corpus luteum related to pregnancy is responsible for formation of ‘‘secondary’’ multiple corpora lutea or at least of a critical mass of luteinised granulosa cells, which could induce a massive release of vasoactive mediators leading to the development of the syndrome [11]. One of the prerequisite in the development of sOHSS could be interaction between hCG and FSH receptor, and it is likely that hCG could stimulate mutated FSH receptor at a threshold which would vary with the type of mutation [11]. Six different classifications are cited in literature whose grades are arranged as per the severity (i.e. mild, moderate and severe) of the disease [14]. In order to simplify the classification of OHSS, we use a classification system adapted and proposed by the Royal College of Obstetricians & Gynaecologists in 2006. We identify mild OHSS, in which patients have abdominal bloating and mild abdominal pain; moderate OHSS, characterised by nausea, vomiting, moderate abdominal pain and ultrasound evidence of ascites; severe OHSS, identifiable by clinical ascites, oliguria, haematocrit 445% and hypoproteinemia; and critical OHSS, with tense ascites, oliguria or anuria, hematocrit455% and white blood count 425 000 [15,16].
Gynecol Endocrinol, Early Online: 1–3
sOHSS due to increased hCG concentrations has comparatively more risk of poor outcome than sOHSS with hypothyroidism. In the later case, normal hCG levels and hormone replacement therapy probably led to a less complicated course of disease and a full-term delivery [10]. Continuation of pregnancy is recommended by many authors as the disease is self-limiting [18]. Another rare event which complicates spontaneous OHSS is ovarian accidents, such as torsion and rupture. Right adnexal torsion is more common than left, though bilateral has also been reported [19]. Differential diagnosis Ultrasonography and CT scan or MRI can be used for exclusion of diagnosis of ovarian cancer. In OHSS, it reveals the classical ‘‘spoke wheel’’ appearance, which is characteristic of theca lutein cysts without solid components [17]. Through close observational management and USG follow-up, OHSS can be differentiated from other differentials [17]. In a report, diagnosis of reactive pituitary hyperplasia was confirmed by the regression of the patient’s mass after thyroid hormone replacement therapy. The main differential diagnosis was a TSH secreting macroadenoma, which is an extremely rare tumour that would not have shrunk in response to thyroid hormone replacement therapy [20]. Laboratory and imaging studies In the report of Dieterich et al., importance of genetic testing in patients of spontaneous OHSS and in patients undergoing infertility treatment is emphasised who can commonly develop OHSS grade III [21]. Genetic testing of patients can be done using DNA sequencing of the FSH receptor gene, plasmid construction, site-directed mutagenesis, cell culture, transient transfection, luciferase assay, immunoprecipitation and immunoblot, immunofluorescent study, cell proliferation assay and camp assay. Serial ultrasonographic examinations are the preferable method to follow-up. Multiple cystic enlargements of ovaries along with accumulation of fluid in peritoneum or pleura though not specific are one of the main radiological finding in cases of spontaneous OHSS [20]. Multiple, enlarged follicles arranged peripherally around a central stroma form a classic soap-bubble or wheel-spoke appearance of the ovarian cystic mass, and even though such findings are consistent with a benign cystic mass or a borderline ovarian neoplasm, they are often observed in cases of OHSS [20]. As in the report of Kanza et al., elevated serum CA125 may also be seen in sOHSS, although several other conditions like hypothyroidism and serous membrane irritation (including peritoneum and pleura) along with neoplastic tumours produce CA-125 [20]. Treatment modalities Behavioural therapy Constant psychological support and counselling of patient play a very important role in management of this condition. The patient should be informed about this condition; even though very rare, it is widely known and affects patients across the world. It spontaneously resolves after pregnancy, and even in the presence of complications, pregnancy can be successfully carried on [7].
Complication
Pharmacotherapy & surgery
Symptoms of OHSS in pregnant patients may be deteriorated by rising level of the endogenous hCG which would lead to a more complicated course of disease as in patients with hypothyroidism [17].
Patients with spontaneous OHSS should be managed conservatively and treatment should be tailored according to severity of symptoms. According to the clinical scenario, intravenous albumin infusions and interventions like peritoneal and pleural
Gynecol Endocrinol Downloaded from informahealthcare.com by University of Otago on 07/26/15 For personal use only.
DOI: 10.3109/09513590.2015.1037268
drainage should be carried out in order to improve the outcome and prevent worsening of symptoms [7]. In cases of OHSS associated with pituitary gonadotroph adenomas, excision of pituitary adenoma can cause regression of the enlarged multicystic ovaries and restoration of regular menstrual cycle, but recurrence is common [21]. Pituitary irradiation is another alternative option, but its effect appears several years after treatment on the tumour mass and on the hormonal hypersecretion [21]. In selected patients with clinically functioning gonadotroph adenomas, in addition to the other treatment modalities like pituitary excision and irradiation, somatostatin analog like octreotide can be used as a reasonable good option [21]. Patients suffering from OHSS complicated by hypothyroidism can be treated with levothyroxine [17]. Partial to complete regression of ovarian cyst was seen from 3 to 6 months and may be during pregnancy or after delivery [17]. However, as in the report of Borna et al., if ovarian cysts do not regress despite of thyroid hormone replacement therapy and observational treatment, conservative surgery should be done, in cases of spontaneous OHSS. But still, in some specific cases, longer observational management without surgical intervention is advised [22]. Since, surgical management of sOHSS increases risk of abortion; it is advised only in cases of follicular rupture, haemorrhage or torsion of ovarian cyst [22]. Another interesting modality of treatment is the use of Cabergoline either alone or in combination with albumin since it is associated with decreased incidence for moderate to severe forms of OHSS. Although not proven, Cabergoline is thought to act by counteracting the increased production of vascular endothelial growth factor (VEGF) by the follicles after hCG administration, the key process leading to OHSS [23].
Conclusion OHSS is an uncommon identity due to variable number of causes, gestation and gestational disease being more common than thyroiditis and other causes. We not only highlight the importance of diagnosis of sOHSS, but also emphasize that diagnosis of sOHSS and its etiology can be completely evaluated radiologically. Biochemical markers will confirm the radiological diagnosis.
Declaration of interest The authors declare that they have no conflict of interest. The manuscript was not presented as part at a meeting or anywhere that might be regarded as redundant publication of the same or very similar work. The manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work. Criteria for inclusion in the authors’/contributors’ list A – conception, B – writing the manuscript, C – Analysis, D – editing. All authors participated in activities A–D.
References 1. Taher BM, Ghariabeh RA, Jarrah NS, et al. Spontaneous ovarian hyperstimulation syndrome caused by hypothyroidism in an adult. Eur J Obstet Gynecol Reprod Biol 2004;112:107–9. 2. Kasum M, Oreskovic´ S, Jezek D. Spontaneous ovarian hyperstimulation syndrome. Coll Antropol 2013;37:653–6. 3. Binder H, Dittrich R, Hager I, et al. Association of FSH receptor and CYP19A1 gene variations with sterility and ovarian hyperstimulation syndrome. Reproduction 2008;135:107–16.
Spontaneous ovarian hyperstimulation syndrome
3
4. He C, Huang H, Song Y. A spontaneous and severe case of ovarian hyperstimulation syndrome after delivery. Gynecol Endocrinol 2008;24:171–2. 5. Suzuki S. Comparison between spontaneous ovarian hyperstimulation syndrome and hyperreactio luteinalis. Arch Gynecol Obstet 2004;269:227–9. 6. Kim MK, Won HJ, Shim SH, et al. Spontaneous ovarian hyperstimulation syndrome following a thawed embryo transfer cycle. Clin Exp Reprod Med 2014;41:140–5. 7. Di Carlo C, Savoia F, Gargano V, et al. Successful pregnancy complicated by spontaneous, familial, recurrent ovarian hyperstimulation syndrome: report of two cases. Gynecol Endocrinol 2013; 29:897–900. 8. Di Carlo C, Savoia F, Fabozzi A, et al. A case of ovarian torsion in a patient carrier of a FSH receptor gene mutation previously affected by spontaneous ovarian hyperstimulation syndrome. Gynecol Endocrinol 2014;31:105–8. 9. De Leener A, Montanelli L, Van Durme J, et al. Presence and absence of follicle-stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome physiopathology. J Clin Endocrinol Metab 2006;91:555–62. 10. Dieterich M, Bolz M, Reimer T, et al. Two different entities of spontaneous ovarian hyperstimulation in a woman with FSH receptor mutation. Reprod Biomed Online 2010;20:751–8. 11. Delbaere A, Smits G, Olatunbosun O, et al. New insights into the pathophysiology of ovarian hyperstimulation syndrome. What makes the difference between spontaneous and iatrogenic syndrome? Hum Reprod 2004;19:486–9. 12. Uchida S, Uchida H, Maruyama T, et al. Molecular analysis of a mutated FSH receptor detected in a patient with spontaneous ovarian hyperstimulation syndrome. PLoS One 2013;8:e75478. 13. Michaelson-Cohen R, Altarescu G, Beller U, et al. Does elevated human chorionic gonadotropin alone trigger spontaneous ovarian hyperstimulation syndrome? Fertil Steril 2008;90:1869–74. 14. Ahmed Kamel RM. Spontaneous ovarian hyperstimulation syndrome in a naturally conceived singleton pregnancy. Fertil Steril 2010;94:351.e1–4. 15. Rachad M, Chaara H, Zahra Fdili F, et al. Ovarian hyperstimulation syndrome in a spontaneous pregnancy with invasive mole: report of a case. Pan Afr Med J 2011;9:23. 16. Alper MM, Smith LP, Sills ES. Ovarian hyperstimulation syndrome: current views on pathophysiology, risk factors, prevention, and management. J Exp Clin Assist Reprod 2009;6:3. 17. Langroudi RM, Amlashi FG, Emami MH. Ovarian cyst regression with levothyroxine in ovarian hyperstimulation syndrome associated with hypothyroidism. Endocrinol Diabetes Metab Case Rep 2013: EDM130006. doi: 10.1530/EDM-13-0006. 18. Oztekin O, Soylu F, Tatli O. Spontaneous ovarian hyperstimulation syndrome in a normal singleton pregnancy. Taiwan J Obstet Gynecol 2006;45:272–5. 19. Munshi S, Patel A, Banker M, Patel P. Laparoscopic detorsion for bilateral ovarian torsion in a singleton pregnancy with spontaneous ovarian hyperstimulation syndrome. J Hum Reprod Sci 2014;7: 66–8. 20. Kanza RE, Gagnon S, Villeneuve H, et al. Spontaneous ovarian hyperstimulation syndrome and pituitary hyperplasia mimicking macroadenoma associated with primary hypothyroidism. World J Radiol 2013;28;5:20–4. 21. Karapanou O, Tzanela M, Tamouridis N, Tsagarakis S. Gonadotroph pituitary macroadenoma inducing ovarian hyperstimulation syndrome: successful response to octreotide therapy. Hormones (Athens) 2012;11:199–202. 22. Borna S, Nasery A. Spontaneous ovarian hyperstimulation in a pregnant woman with hypothyroidism. Fertil Steril 2007;88: 705.e1–3. 23. Leitao VM, Moroni RM, Seko LM, et al. Cabergoline for the prevention of ovarian hyperstimulation syndrome: systematic review and meta-analysis of randomized controlled trials. Fertil Steril 2014; 101:664–75.
REVIEW ARTICLE
Spontaneous ovarian hyperstimulation syndrome – understanding the dilemma Amit Kumar Dey1, Abhishek Dubey1, Kartik Mittal2, and Sunita Kale2 Department of General Surgery and 2Department of Radiology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
Gynecol Endocrinol Downloaded from informahealthcare.com by University of Otago on 07/26/15 For personal use only.
1
Abstract
Keywords
Ovarian hyper-stimulation syndrome (OHSS) is an uncommon identity due to variable number of causes, gestation and gestational disease being more common than thyroiditis and other causes. The role of radiology and biochemical markers are of utmost importance in not only diagnosing spontaneous ovarian hyper-stimulation syndrome (sOHSS) but also ruling out other cystic ovarian diseases and to determine the underlying aetiology and course of the disease. Understanding its pathophysiology and genetics holds the key to unravel the mysteries of this condition.
Gonadotropin, ovarian hyper stimulation syndrome, spontaneous
Introduction Classically, ovarian hyper-stimulation syndrome (OHSS) is described as one of the side-effects in women who receive gonadotropins for induction of ovulation during assisted reproductive technology (ART) procedure [1]. However, of all stimulation cycles in assisted reproduction, the prevalence of severe form of OHSS is quite small, ranging from 0.5 to 5% or from 0.2 to 1%, as calculated by the World Health Organization [2]. Along with enlarged and polycystic ovary, ascites, pleural effusion, haemoconcentration, hypovolemia, renal failure, oliguria, thromboembolic episodes, adult respiratory distress syndrome and death may occur in severe OHSS [1,3]. It seems that when human chorionic gonadotropin (hCG) is administered, there is an increase in capillary permeability due to release of certain substances; although the pathogenesis has not been completely explained [4]. It is commonly reported in women with polycystic ovary syndrome, hypothyroidism, gonadotroph pituitary adenoma and pregnancy [1,5]. Spontaneous OHSS (sOHSS) has been reported to be associated with elevated hCG levels (either exogenously administered or as a result of endogenous pregnancy-derived hCG stimulation) and increased endothelial growth factor [5,6]. CA125 has also been reported to increase in spontaneous OHSS, but its measurement is not useful for arriving at a differential diagnosis [5]. Hyperreeactio luteinalis (HL) is another rare condition, mimicking sOHSS, which occurs during spontaneous pregnancy and is characterized by multicystic and bilateral enlargement of
Address for correspondence: Kartik Mittal, 3rd year MD, Department of Radiology, Seth GS Medical College and KEM Hospital, Room no. 107, Main boy’s hostel, Acharya Donde Marg, Parel, Mumbai – 400012, Maharashtra, India. Tel: +91-8080995687. E-mail: amit3kem@ gmail.com
History Received 19 January 2015 Revised 18 March 2015 Accepted 31 March 2015 Published online 20 July 2015
ovaries associated with high level of maternal serum hCG and hyperandrogenic state [5]. It is caused by high-beta hCG levels or abnormal beta hCG receptor sensitivity [7]. Since, pathogenesis of spontaneous OHSS and/or HL is not completely elucidated, it is difficult to differentiate spontaneous OHSS from HL if the onset is early in the first trimester [5].
Pathophysiology and genetics The report of Carlo et al. seemed to suggest the hypothesis of a genetic predisposition for spontaneous OHSS [7]. There are two main theories explaining the mechanism of occurrence of spontaneous OHSS viz. hyper-secretion of glycoprotein hormone and/or mutation of follicle stimulating hormone (FSH) receptor [8–10]. Spontaneous OHSS is usually reported during pregnancy. Many of them were observed during multiple pregnancies or hydatidiform moles having high-hCG concentration, while others presented with hypothyroidism in which high levels of thyroid stimulating hormone (TSH) have a suggestive role in ovarian stimulation [11]. In corpus luteum, the expression of FSH receptor decreases drastically, while in granulosa cells of developing follicles it remains constant during pregnancy. As serum FSH falls to a very low level, FSH receptors are not weakly stimulated, while hCG hyperstimulates the mutated FSH receptor expressed in developing follicles during pregnancy [11]. The follicles start growing, enlarge and finally acquire luteinising hormone (LH) receptors on granulosa cells, which may also be stimulated by hCG, inducing follicular luteinisation together with the secretion of vasoactive molecules responsible for the development of the syndrome [11]. Cohorts of follicles competent enough to achieve pre-ovulatory status within 10–14 days and which undergoes subsequent luteinisation under the action of hCG exist during pregnancy.
Gynecol Endocrinol Downloaded from informahealthcare.com by University of Otago on 07/26/15 For personal use only.
2
A. K. Dey et al.
In some of the secondarily recruited follicles, possibly premature luteinisation may occur [11]. As a result of multiple corpora lutea formation, there is association with active angiogenesis and increased capillary permeability leading to sOHSS. Massive release of vasoactive mediators exacerbating local inflammatory like reactions accompanying angiogenesis during corpora lutea formation may be induced by luteinisation of enlarged super stimulated ovaries [11]. Physiological control mechanism can be overstretched as the release of vasoactive molecules reaches a threshold, leading to the development of symptoms of OHSS [11]. Another possible underlying mechanism, though not fully understood, is hypergonadotropinemia caused by gonadotropinproducing pituitary adenoma [12]. Women in reproductive age with these FSH-producing pituitary adenomas exhibit spontaneous OHSS characterised by high-serum FSH and estradiol levels along with massive multicystic ovaries [12]. In some of the cases reported, FSH secreting pituitary adenoma associated with sOHSS has almost normal FSH level, and in few of these cases estradiol level was elevated [12]. Interestingly, enhanced bioactivity of FSH produced from FSH-producing adenoma is also reported, thereby aggravating OHSS even when within normal range [12]. However, in the report of Michaelson-Cohen et al. despite of high-hCG concentrations, there are many other factors triggering spontaneous OHSS. Some of these include variant hCG having high-biological activity; generation of other factors like vascular endothelial growth factor (VEGF) or having activity similar to VEGF sparked by hCG, elevated placental hormones such as estradiol promoting granulosa cell proliferation or granulose cell proliferation being more sensitive to stimulation of FSHr [13]. Clinical signs and symptoms In contrast to the iatrogenic OHSS which is usually reported to develop between 3 and 5 months, spontaneous OHSS generally starts from 8 to 14 weeks of amenorrhea [11]. However, activity of corpus luteum diminishes from 5th week of pregnancy in spite of increasing hCG level [11]. As in the report of Delbaere et al. during sOHSS, the ‘‘initial’’ corpus luteum related to pregnancy is responsible for formation of ‘‘secondary’’ multiple corpora lutea or at least of a critical mass of luteinised granulosa cells, which could induce a massive release of vasoactive mediators leading to the development of the syndrome [11]. One of the prerequisite in the development of sOHSS could be interaction between hCG and FSH receptor, and it is likely that hCG could stimulate mutated FSH receptor at a threshold which would vary with the type of mutation [11]. Six different classifications are cited in literature whose grades are arranged as per the severity (i.e. mild, moderate and severe) of the disease [14]. In order to simplify the classification of OHSS, we use a classification system adapted and proposed by the Royal College of Obstetricians & Gynaecologists in 2006. We identify mild OHSS, in which patients have abdominal bloating and mild abdominal pain; moderate OHSS, characterised by nausea, vomiting, moderate abdominal pain and ultrasound evidence of ascites; severe OHSS, identifiable by clinical ascites, oliguria, haematocrit 445% and hypoproteinemia; and critical OHSS, with tense ascites, oliguria or anuria, hematocrit455% and white blood count 425 000 [15,16].
Gynecol Endocrinol, Early Online: 1–3
sOHSS due to increased hCG concentrations has comparatively more risk of poor outcome than sOHSS with hypothyroidism. In the later case, normal hCG levels and hormone replacement therapy probably led to a less complicated course of disease and a full-term delivery [10]. Continuation of pregnancy is recommended by many authors as the disease is self-limiting [18]. Another rare event which complicates spontaneous OHSS is ovarian accidents, such as torsion and rupture. Right adnexal torsion is more common than left, though bilateral has also been reported [19]. Differential diagnosis Ultrasonography and CT scan or MRI can be used for exclusion of diagnosis of ovarian cancer. In OHSS, it reveals the classical ‘‘spoke wheel’’ appearance, which is characteristic of theca lutein cysts without solid components [17]. Through close observational management and USG follow-up, OHSS can be differentiated from other differentials [17]. In a report, diagnosis of reactive pituitary hyperplasia was confirmed by the regression of the patient’s mass after thyroid hormone replacement therapy. The main differential diagnosis was a TSH secreting macroadenoma, which is an extremely rare tumour that would not have shrunk in response to thyroid hormone replacement therapy [20]. Laboratory and imaging studies In the report of Dieterich et al., importance of genetic testing in patients of spontaneous OHSS and in patients undergoing infertility treatment is emphasised who can commonly develop OHSS grade III [21]. Genetic testing of patients can be done using DNA sequencing of the FSH receptor gene, plasmid construction, site-directed mutagenesis, cell culture, transient transfection, luciferase assay, immunoprecipitation and immunoblot, immunofluorescent study, cell proliferation assay and camp assay. Serial ultrasonographic examinations are the preferable method to follow-up. Multiple cystic enlargements of ovaries along with accumulation of fluid in peritoneum or pleura though not specific are one of the main radiological finding in cases of spontaneous OHSS [20]. Multiple, enlarged follicles arranged peripherally around a central stroma form a classic soap-bubble or wheel-spoke appearance of the ovarian cystic mass, and even though such findings are consistent with a benign cystic mass or a borderline ovarian neoplasm, they are often observed in cases of OHSS [20]. As in the report of Kanza et al., elevated serum CA125 may also be seen in sOHSS, although several other conditions like hypothyroidism and serous membrane irritation (including peritoneum and pleura) along with neoplastic tumours produce CA-125 [20]. Treatment modalities Behavioural therapy Constant psychological support and counselling of patient play a very important role in management of this condition. The patient should be informed about this condition; even though very rare, it is widely known and affects patients across the world. It spontaneously resolves after pregnancy, and even in the presence of complications, pregnancy can be successfully carried on [7].
Complication
Pharmacotherapy & surgery
Symptoms of OHSS in pregnant patients may be deteriorated by rising level of the endogenous hCG which would lead to a more complicated course of disease as in patients with hypothyroidism [17].
Patients with spontaneous OHSS should be managed conservatively and treatment should be tailored according to severity of symptoms. According to the clinical scenario, intravenous albumin infusions and interventions like peritoneal and pleural
Gynecol Endocrinol Downloaded from informahealthcare.com by University of Otago on 07/26/15 For personal use only.
DOI: 10.3109/09513590.2015.1037268
drainage should be carried out in order to improve the outcome and prevent worsening of symptoms [7]. In cases of OHSS associated with pituitary gonadotroph adenomas, excision of pituitary adenoma can cause regression of the enlarged multicystic ovaries and restoration of regular menstrual cycle, but recurrence is common [21]. Pituitary irradiation is another alternative option, but its effect appears several years after treatment on the tumour mass and on the hormonal hypersecretion [21]. In selected patients with clinically functioning gonadotroph adenomas, in addition to the other treatment modalities like pituitary excision and irradiation, somatostatin analog like octreotide can be used as a reasonable good option [21]. Patients suffering from OHSS complicated by hypothyroidism can be treated with levothyroxine [17]. Partial to complete regression of ovarian cyst was seen from 3 to 6 months and may be during pregnancy or after delivery [17]. However, as in the report of Borna et al., if ovarian cysts do not regress despite of thyroid hormone replacement therapy and observational treatment, conservative surgery should be done, in cases of spontaneous OHSS. But still, in some specific cases, longer observational management without surgical intervention is advised [22]. Since, surgical management of sOHSS increases risk of abortion; it is advised only in cases of follicular rupture, haemorrhage or torsion of ovarian cyst [22]. Another interesting modality of treatment is the use of Cabergoline either alone or in combination with albumin since it is associated with decreased incidence for moderate to severe forms of OHSS. Although not proven, Cabergoline is thought to act by counteracting the increased production of vascular endothelial growth factor (VEGF) by the follicles after hCG administration, the key process leading to OHSS [23].
Conclusion OHSS is an uncommon identity due to variable number of causes, gestation and gestational disease being more common than thyroiditis and other causes. We not only highlight the importance of diagnosis of sOHSS, but also emphasize that diagnosis of sOHSS and its etiology can be completely evaluated radiologically. Biochemical markers will confirm the radiological diagnosis.
Declaration of interest The authors declare that they have no conflict of interest. The manuscript was not presented as part at a meeting or anywhere that might be regarded as redundant publication of the same or very similar work. The manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work. Criteria for inclusion in the authors’/contributors’ list A – conception, B – writing the manuscript, C – Analysis, D – editing. All authors participated in activities A–D.
References 1. Taher BM, Ghariabeh RA, Jarrah NS, et al. Spontaneous ovarian hyperstimulation syndrome caused by hypothyroidism in an adult. Eur J Obstet Gynecol Reprod Biol 2004;112:107–9. 2. Kasum M, Oreskovic´ S, Jezek D. Spontaneous ovarian hyperstimulation syndrome. Coll Antropol 2013;37:653–6. 3. Binder H, Dittrich R, Hager I, et al. Association of FSH receptor and CYP19A1 gene variations with sterility and ovarian hyperstimulation syndrome. Reproduction 2008;135:107–16.
Spontaneous ovarian hyperstimulation syndrome
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