The Ovary

Peter C.K. Leung, Eli Y. Adashi, Peter C. K. Leung, Eli Y. Adashi

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128132104
• Edition: 3
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

The Ovary, Third Edition, includes more than 60% new material that highlights the clinical aspects of human ovarian functions. It covers advances in the areas of genomics, assisted reproductive technology, and cancer diagnosis and treatment. This updated edition synthesizes new information at the molecular, cellular and organismal levels, while also presenting modern ovarian physiology in a more understandable and comparative context. The book looks at ovarian function from a detailed molecular and cellular level that examines all phases of the ovarian lifecycle that places special emphasis on the pathophysiology of the human ovary, including ovarian carcinogenesis.

• Represents an unparalleled compilation of chapters that are relevant to contemporary ovarian physiology
• Provides basic and clinical research on ovarian function, abnormalities, assisted reproductive technology, and cancer
• Highlights contemporary strategies and treatment paradigms in female factor infertility

V

Human Ovarian Pathophysiology: Select Aspects

Chapter 22

Ovarian Hyperstimulation Syndrome

Nuria Pellicer; Daniela Galliano; Antonio Pellicer

Abstract

Ovarian hyperstimulation syndrome (OHSS) is a complication resulting from infertility treatments. The syndrome consists of a series of signs and symptoms which are the consequence of increased ovarian capillary permeability after hCG administration. Pain and discomfort due to enlarged ovaries, ascites, hypercoagulability, and reduced renal function are common findings. OHSS is usually mild, but can be complicated seriously and become a life-threatening condition, especially in women who become pregnant. Therefore, cryopreservation of oocytes/embryos to defer pregnancy for a subsequent cycle is a crucial step in the prevention of OHSS. Some phenotypic characteristics (polycystic ovarian syndrome) and biomarkers of ovarian reserve (antral follicle count and serum antimüllerian hormone levels) predict the development of OHSS in infertile patients, and therefore special protocols for ovarian stimulation should be employed to minimize risks. When OHSS develops, treatment consists of the management of symptoms and monitoring of vital signs, including culdocentesis of ascitic fluid, intravenous liquid replacement, antithrombotic measures, and pain reduction.

Keywords

Ovarian hyperstimulation syndrome; Assisted reproduction technologies; In vitro fertilization; Ovarian stimulation; Vascular endothelial growth factor; Ascites; Thromboembolism; Polycystic ovarian syndrome; Ovarian cyst

Abbreviations

AFC anfral follicle count

AMH anti-müllerian hormone

ARDS acute respiratory distress syndrome

ART assisted reproduction technologies

BMI body mass index

Ca calcium

COS controlled ovarian stimulation

DIC disseminated intravascular coagulation

DOPAC 3,4-dihydroxyphenyl-acetic acid

FSH follicle-stimulating hormone

GC granulosa cell

hCG human chorionic gonadotropin

HES hydroxyethyl starch solution

IO induction of ovulation

IVF in vitro fertilization

IVM in vitro maturation

Kp kisspeptin

OHSS ovarian hyperstimulation syndrome

VEGF vascular endothelial growth factor

VPF vascular permeability factor

Definition and Prevalence

Ovarian hyperstimulation syndrome (OHSS) is the most serious complication resulting from the medical manipulation of the ovary. It occurs in anovulatory patients wanting to conceive who need full ovulation induction (OI), and in controlled ovarian stimulation (COS) in women undergoing assisted reproduction technologies (ART) in whom the retrieval of a certain number of oocytes is desired. Thus, OHSS is an iatrogenic condition, which affects young healthy individuals mainly as a consequence of fertility treatments.

OHSS consists of a broad spectrum of signs and symptoms that include abdominal distention and discomfort, enlarged ovaries, ascites, and other complications of enhanced ovarian vascular permeability [1,2]. In its severe form, OHSS is a life-threatening condition because it can cause renal failure and venous or arterial thromboembolic events, which include stroke and loss of perfusion to an extremity. It has also been associated with maternal death [3]. In addition, there is an important economic burden associated with OHSS due to absence from work, bed rest, and hospitalization, as well as the intensive medical management of severe cases.

The true incidence of OHSS is difficult to determine as there is no generally accepted definition of the syndrome. Moreover, it depends upon the clinical setting (OI or COS), the drugs employed, and the type of patient treated (either at risk or not at risk). When ovulation is induced with clomiphene citrate or aromatase inhibitors, either for timed intercourse or intrauterine insemination, a mild form of OHSS may occur, but moderate to severe OHSS is rarely seen [4]. In COS, the overall incidence of moderate and severe OHSS is 3%–6% and 0.1%–2%, respectively [1,5,6]. Hospitalization due to OHSS has been reported to range between 0.3% and 1.1% [7,8]. There was an alarming increase in the incidence of OHSS in the 1990s. However, the introduction of risk markers and a series of preventative measures, the most important of which is the freezing the embryos avoiding pregnancies, has resulted in a substantial decrease of this iatrogenic complication.

Pathogenesis

OHSS is the result of multiple follicular development with gonadotropins and subsequent ovulation triggering with hCG. If pregnancy follows, trophoblast-derived hCG will worsen the symptoms. Also, it has to be recognized as a phenomenon localized to the ovaries. In fact, although increased peripheral arteriolar dilatation in the entire body was proposed [9], it is today accepted that OHSS is a local phenomenon of the ovary, since oophorectomy restores normality and OHSS does not develop in experimental conditions in which ovaries are not present [10,11]. Similarly, if as a result of COS with gonadotropins many follicles develop and hCG for ovulation triggering is withhold, OHSS does not occur [12–14], showing that hCG is the driver of all the pathophysiological events in OHSS. Since hCG has no direct vasoactive properties, investigations have aimed to detect the vasoactive substance responsible for this condition.

Initial investigations suggested that high estradiol levels was the determinant of OHSS [15,16]. However, women with enzymatic mutations in the steroid pathway and low estrogens levels in the blood can develop OHSS [17]. Others have pointed to substances present in follicular and ascitic fluid of hyperstimulated women such as cytokines and growth factors (interleukins (IL): IL-2, IL-6, IL-8, IL-10, IL-18) [18], as well as other substances such as histamine, prolactin, prostaglandins, and renin-angiotensin as participants in OHSS pathophysiology [19].

The true candidate must fulfill a number of prerequisites. Its expression should be enhanced by hCG and should be higher in cases of OHSS. It must have a clear and strong effect on vascular permeability, and inhibition of this candidate mediator should inhibit the clinical manifestations of OHSS. Today, it is accepted that the hCG mediator is vascular endothelial growth factor (VEGF), originally described as a vascular permeability factor (VPF) because of its ability to cause substantial vascular leakage [20] when secreted by tumor cells. Compared with histamine, VEGF/VPF enhances endothelial permeability by 50,000 times [21].

The human VEGF gene has been mapped to chromosome 6p12 [22] and is made up of eight exons. The VEGF gene shows the same exonic structure in rodents and humans, with 95% protein homology between them [23]. Similar to the human [24], hybridization studies in the rat ovary have demonstrated significant VEGF mRNA expression, which are mostly seen after the LH surge [25].

VEGF exerts its biological actions by binding to receptors present on the endothelial cells surface that belong to the tyrosine kinase receptor family [26], VEGFR-1 (Flt-1) and VEGFR-2 (Flk1/KDR) [26,27]. The receptor Flk1/KDR appears to be involved in regulating vascular permeability, angiogenesis, and vasculogenesis, wh...