Indications for Abdominal Surgery in Spontaneous Ovarian Hyperstimulation: A Literature Review

Abstract

Objective:

Ovarian hyperstimulation syndrome (OHSS) is a well-known phenomenon in reproductive medicine, complicating assisted reproduction for 1%–10% of women. When the same phenomenon occurs without ovulation induction, it is called spontaneous ovarian hyperstimulation syndrome (sOHSS). This extremely rare condition can be mistaken for other serious and more-prevalent conditions. There are algorithms proposed to guide the diagnosis. However, none of those algorithms include the role of surgical intervention to the best of our knowledge. This review of published literature on sOHSS evaluates the indications and types of abdominal surgical interventions in cases of sOHSS.

Methods:

A review of literature through medical electronic databases was carried out to describe the previously reported cases and the indications for abdominal surgical interventions in such cases until the end of 2016. Neonatal sOHSS cases were excluded.

Results:

Seventy-four cases were reported in 60 articles. The mean age of the women was 27 ± 6.96 years, with the youngest being 12 and the oldest being 40. One case had sOHSS in 4 consecutive pregnancies and another had it in her seventh pregnancy for the first time. Abdominal surgical intervention other than cesarean section was performed in one-third (20/74) of the patients. Suspicion of ovarian malignancy was the commonest indication for abdominal surgery in 55%. Other indications were management of suspected ovarian torsion or ovarian bleeding, therapeutic ascetic tap, and resection of ovarian tissue to decrease disease burden.

Conclusions:

sOHSS is a rare condition that needs to be kept in the differential diagnosis when the clinical picture is suggestive. The most-common indication for abdominal nonobstetric surgical intervention in such cases is suspicion of ovarian malignancy. When following the algorithms proposed for the diagnosis are not conclusive, conservative and principally diagnostic surgical intervention should be the approach.

Introduction

Ovarian hyperstimulation syndrome (OHSS) is a well-known phenomenon in reproductive medicine, complicating assisted reproduction in 1–10% of women undergoing the procedure¹ When the same phenomenon occurs without ovulation induction, it is called spontaneous ovarian hyperstimulation syndrome (sOHSS). This spontaneous syndrome was described in the medical literature in 1955.² However, the term spontaneous hyperstimulation was first used by Leis et al in 1978.³ sOHSS is an extremely rare—but well-described—phenomenon. De Leener et al. described the types of sOHSS according to etiology,⁴ and that classification was modified further by Panagiotopoulou et al.⁵ The etiology can be a mutant follicular-stimulating hormone (FSH) receptor gene, a high-level of human chorionic gonadotrophin (hCG), or a high level of FSH or luteinizing hormone (LH). The grading system of sOHSS is the same used for its iatrogenic counterpart, involving clinical, radiologic, and laboratory features.^6,7

As sOHSS is a rare entity, it can be life-threatening and easily confused with other serious diagnoses, the literature has described algorithms to guide its diagnostic process.^5,8 However, none of those proposed algorithms involve surgical intervention. This reflects that those algorithms assume that sOHSS is in the mind of the treating physician or that the answer is always clear from the algorithm. The role of abdominal surgical intervention in cases of ovarian masses can be for diagnostic or therapeutic purposes.^9–11

This literature review of the published literature on sOHSS was conducted to explore the indications for nonobstetric abdominal surgical intervention in reported cases of sOHSS.

Methods

A review of literature through medical electronic databases was carried out to describe previously reported cases of sOHSS. The search included Medline,^® SCOPUS, EMBASE, Cumulative Index to Nursing and Allied Health Literature, and Google Scholar using the keywords spontaneous ovarian hyperstimulation syndrome, spontaneous ovarian stimulation, ovarian hyperstimulation syndrome, and spontaneous. The end of the last timeperiod searched was December 30, 2016. The cases that had titles, abstracts, and/or full texts in English were identified. In addition, when the full text was not available in English but the text was translated to English from the original language—including Chinese,¹¹ Portuguese,¹² and Italian¹³—were included. The cases retrieved were reviewed individually to confirm eligibility. There were some additional cases referenced in some of the non-English articles but those were not included, as they did not meet this review's criteria for language. The cases reported in consecutive pregnancies were included as separate cases but multiple reports of the same pregnancy were excluded.

A database was created detailing the demographics, symptoms, investigations, final diagnosis, and the outcome in each case, with special attention to cases that had abdominal surgical intervention other than cesarean section.

Results

A total of 93 cases were published in literature as of December 2016 with diagnoses of sOHSS. Of the reported cases, 19 were reported in newborns and were excluded. In addition, a case of a thawed IVF cycle was excluded because of concern of an iatrogenic component in the etiology of the patient's OHSS.¹⁴ After these exclusions, there were 74 sOHSS cases reported in 60 articles. Of those, 64% (48/74) were associated with pregnancy (see Table 1) and the remaining 26 were nonpregnant patients. The mean age of women with sOHSS was 27 ± 6.96 years, with the youngest at age 12 and the oldest at age 40. The mean gravidity of those women was 1.3 ± 1.52, and the mean parity was 0.5 ± 1.23. One case had sOHSS in 4 consecutive pregnancies and another woman had it in her seventh pregnancy for the first time.¹⁵ The commonest presenting symptom was abdominal discomfort/pain in 70% (52/74) of these women. The gestational age at presentation varied from 6 to 22 weeks; although the commonest was 7–14 weeks in (39/48) cases. The severity of the condition varied from mild to critical, with 39% (29/74) having grade III OHSS or worse.

Table 1.

Classification of sOHSS Cases Based on Etiology

Type of sOHSS	Etiology		Total sOHSS cases	Surgical intervention for sOHSS
I	FSHr mutation	Familial	9	1⁹
II	High hCG level	Complete/partial mole	11	3^13,16,17
		Placental mesenchymal dysplasia	1	0
		Mediastinal choriocarcinoma	1	0
		Singleton pregnancy & elevated hCG level	6	0
		Twins	2	1³
III	High TSH level	Hypothyroidism	20	3^10,18,19
IV	High FSH Level	Gonadotropin-producing pituitary adenoma Ectopic FSH secretion	18 1	7^20–26
Presumed idiopathic	—	Singleton pregnancies with no identified cause or FSHr mutation not tested	5	5^11,27–30

sOHSS, spontaneous ovarian hyperstimulation; FSHr, follicle-stimulating hormone receptor; hCG, human chorionic gonadotropin; TSH, thyroid-stimulating hormone; FSH, follicle-stimulating hormone.

Abdominal surgical intervention other than cesarean section was performed for almost one-third (20/74) of the patients. Half of those abdominal surgeries (11/20) were by laparoscopy.

In patients who were operated on, 60% (12/20) of the procedures were associated with intrauterine pregnancies (3 molars, 1 twins, and 8 singletons). Eight of these patients had laparotomy, whereas the other 4 had laparoscopic interventions (see Table 2).

Table 2.

Summary of sOHSS Cases That Had Surgical Interventions

1st author, yr & ref.	Age	Indications	Surgical interventions
1st author, yr & ref.	(in yr)	Indications	Surgical interventions
Hooper, 1966^a	25	Suspected ovarian malignancy/to decrease ovarian tissue volume	Laparotomy, U/L oophorectomy, wedge resection other ovary
Cappa, 1976¹³	25	Suspected ovarian malignancy	Laparotomy, hysterectomy, B/L oophorectomy
Leis, 1978³	28	Suspected ovarian malignancy	Laparotomy
Pentz-Vidovic, 2000^b	23	Suspected PCOS	Laparoscopy, B/L wedge resection of ovaries
Shimon, 2001^c	28	Suspected ovarian torsion	Laparoscopy, B/L ovarian biopsies
Castelbaum, 2002^d	35	Suspected endometriosis for recurrent cysts	Laparoscopy, B/L ovarian biopsies
Baksu 2004^e	26	Suspected ovarian torsion	Laparoscopic ovarian detorsion, aspiration of ovarian cysts
Eftekhar, 2005^f	30	Suspected ovarian torsion	Laparotomy, detorsion, aspiration of ovarian cysts
Özden, 2005²⁷	19	Suspected ovarian malignancy	Laparotomy, aspiration of ovarian cysts
Sultan, 2006^g	12	Suspected intra-abdominal bleeding	Laparoscopy, B/L ovarian biopsies, drainage of ascites
Borna, 2007¹⁰	30	Persistent ovarian cysts after delivery/suspected ovarian malignancy	Laparotomy, aspiration of ovarian cysts
Cooper, 2008^h	40	Ovarian cyst	Ovarian cystectomy
Castelo-Branco, 2009²⁸	31	Suspicion of malignancy/estradiol producing tumor	Laparoscopy, B/L ovarian biopsies
Baba, 2009²⁹	32	Suspected ovarian malignancy	Laparotomy, B/L oophorectomy
Rachad, 2011ⁱ	34	Suspected ovarian malignancy/persistent molar tissue	Laparotomy, hysterectomy
Macchia, 2012³⁰	31	Suspected ovarian malignancy	Laparoscopy, B/L ovarian cystectomy
Lei, 2013¹¹	26	Suspected ovarian malignancy	Laparoscopy, ovarian biopsies
Rajaram, 2015²⁶	19	Suspected ovarian malignancy	Laparotomy, B/L ovarian biopsies
Di Carlo, 2015⁹	29	Suspected ovarian torsion	Laparoscopy, U/L oophorectomy, ovarian biopsy
Munshi, 2014³²	26	Suspected ovarian torsion	B/L detorsion, drainage of ovarian cysts, oophoropexy

sOHSS, spontaneous, ovarian hyperstimulation; yr, year(s); ref., reference; U/L, unilateral; B/L, bilateral; PCOS, polycystic ovarian syndrome.

Hooper A., Mascarenhas AM, O'Sullivan JV. Gross ascites complicating hydatidiform mole. J Obs Gynaecol Br Commonw. 1966;73:854–855.

Pentz-Vidovic I, Skoric T, Grubisic G, et al. Evolution of clinical symptoms in a young woman with a recurrent gonadotroph adenoma causing ovarian hyperstimulation. Eur J Endocrinol. 2000;143(5):607–614.

Shimon I, Rubinek T, Bar-hava I, et al. Ovarian Hyperstimulation without Elevated Serum Estradiol Associated with Pure Follicle-Stimulating Hormone-Secreting Pituitary Adenoma. J Clin Endocrinol Metab. 2015;86(August):3635-3640. doi:0013-7227/01

Castelbaum AJ, Bigdeli H, Post KD, Freedman MF, Snyder PJ. CASE REPORTS Exacerbation of ovarian hyperstimulation by leuprolide reveals a gonadotroph adenoma. Fertil Steril. 2002;78(6):1311–1313.

Baksu A, Baksu B, Goker N. Laparoscopic unwinding and cyst aspiration of an ovarian torsion in spontaneous ovarian hyperstimulation syndrome associated with a singleton pregnancy. Aust N Z J Obstet Gynaecol. 2004;44(3):270–272. doi:10.1111/j.1479-828X.2004.00207.x

Eftekhar Z, Rahimi-Moghaddam P, Yarandi F, Tahmasbi M. An ovarian torsion in severe spontaneous ovarian hyperstimulation syndrome associated with a singleton pregnancy. J Obstet Gynaecol (Lahore). 2005;25(4):393–394. doi:10.1080/01443610500135636

Sultan A, Velaga MR, Fleet M, Cheetham T. Cullen's sign and massive ovarian enlargement secondary to primary hypothyroidism in a patient with a normal FSH receptor. Arch Dis Child. 2006;91(6):509–510. doi:10.1136/adc.2005.088443

h Cooper O, Geller JL, Melmed S. Ovarian hyperstimulation syndrome caused by an FSH-secreting pituitary adenoma. Nat Clin Pract Endocrinol Metab. 2008;4(4):234–238. doi:10.1038/ncpendmet0758

Rachad M, Chaara H, Fdili FZ, Bouguern H, Melhouf A. Ovarian hyperstimulation syndrome in a spontaneous pregnancy with invasive mole: report of a case. Pan Afr Med J. 2011;9(23):1–12.

Suspicion of ovarian malignancy was the commonest indication for the abdominal surgery in 55% (11/20) of the patients (Table 2). Other indications included management of suspected ovarian torsion or ovarian bleeding (6/20); operating for suspected other gynecologic conditions, such as polycystic ovarian syndrome or endometriosis; and therapeutic ascetic tap and resection of ovarian tissue to decrease the disease burden.

Discussion

This literature review showed that sOHSS is rare but that it is a well-described phenomenon in the medical literature. Despite these descriptions, this condition still creates a significant diagnostic dilemma, which is shown by the fact that 70% (13/20) of nonobstetric abdominal surgeries were performed because of suspicion of other diagnoses. sOHSS diagnostic ambiguity is likely to be explained by the fact that the commonest version of OHSS is iatrogenic and—in the absence of a history indicating use of medications to stimulate ovulation—this makes the treating physician think about the next-commonest cause of ovarian enlargement and ascites, which is ovarian malignancy.

When the etiology is related to an obvious source of high hCG, such as gestational trophoblastic disease, choriocarcinoma, or multiple gestation, the diagnostic dilemma of sOHSS is least likely to occur. That might be due to the more-common association of high hCG with what is described as hyperreactio luteinalis.^16–18 The current authors agree with other colleagues that sOHSS is a continuum and that hyperreactio luteinalis is a milder form of sOHSS.¹⁹ Despite this belief, the current authors do see gynecologic references that describe these conditions as two separate entities and they try to distinguish them on some bases that are vague and difficult to define.²⁰

When the hCG production is extragonadal, a the patient is likely to present with symptoms related to the primary source; for example, mediastinal choriocarcinoma presents with cough and hemoptysis.⁸

Adnexal masses occur in 0.2% to 2% of pregnancies, and fewer than 10% of them are malignant.^18,21 Distinguishing sOHSS from ovarian malignancy is not easy with or without pregnancy.²¹ Like sOHSS, ovarian malignancy can occur in any age group. Both conditions involve rapid ovarian growth and elevated cancer antigen 125. However, bilateral ovarian involvement and ultrasonography images of simple cysts and a homogeneous thin wall in a “spoke-wheel” pattern, suggest sOHSS.^21–23 Differentiating the two diagnoses from each other is of paramount importance, because early recognition and intervention is necessary to prevent severe complications of sOHSS, such as thromboembolism and renal failure.^1,6 However, management of ovarian malignancy requires surgical diagnosis and staging.²⁴

Clinical and radiologic diagnostic algorithms for sOHSS have been published and they are helpful guides for physicians.^5,8 In case the diagnosis is still not clear to a physician and ovarian malignancy is still suspected, diagnostic laparoscopy with aspiration of ascitic fluid for cytology and ovarian biopsy for frozen section should be the approach. Many oncologists as well as experienced gynecologists would agree that they might be able to differentiate intraoperatively the likelihood of ovarian malignancy or hyperstimulation, depending on the macroscopic picture. Hyperstimulated ovaries have a multicystic appearance, with thin and almost transparent walls that break easily.^11,25,26 The ascitic fluid in both can be clear, amber, or hemorrhagic.^25,26 The final diagnosis is by histopathologic examination that, it is hoped, comes before the surgeon proceeds to any radical surgical intervention that occasionally is unnecessary.³ In many cases, when ovarian malignancy was suspected, surgical intervention only involved ovarian biopsies and drainage of ascites. That is likely due to the compelling intraoperative findings and /or histopathology results.^{10,11,26–30}

There is a consensus among experts in the field of reproductive medicine that the main management of OHSS is medical and supportive therapy. This agreement has translated into clinical-practice guidelines that assist physicians and gynecologists in managing this condition.⁶ Surgical intervention is recommended in any case of an acute abdomen wherein the clinical picture indicates ovarian torsion or acute ovarian bleeding.³¹ In such cases, the intervention should be limited to detort the ovary or to control the bleeding. If the diagnosis of the nature of the ovarian enlargement is not clear, ovarian biopsy and fluid aspiration is indicated.^9,32 If the diagnosis is clear, leaving in a closed-system drain might be beneficial for drainage as many cases of sOHSS develop significant ascites requiring a peritoneal tap.^6,11 Bilateral partial oophorectomy or wedge resection of one or both ovaries to decrease the burden of disease is not recommended, as this is an aggressive procedure with insufficient evidence of effectiveness to decrease either the severity or the duration of the syndrome.^33,34 It also is likely to have a negative impact on the future hormonal and reproductive functions of the ovaries.

Conclusions

This review shed light on the indications for abdominal surgical intervention in patients with sOHSS. Most of the nonobstetric surgical interventions are due to diagnostic uncertainty and, to a smaller extent, to the acute complications of sOHSS. When diagnostic algorithms do not confirm the diagnosis, complementing them with a conservative and principally diagnostic surgical approach to guide future management is strongly recommended.

Footnotes

Author Disclosure Statement

No financial conflicts of interest exist.

Funding Information

No funding was received for this article.

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