The case
A 25-year-old South Asian woman was referred to an infertility unit owing to her 2-year history of primary infertility. Her menstrual cycle had been irregular and infrequent (<4 cycles per year) in the past decade. The patient also complained of excessive facial hair; otherwise, she had no other notable medical history. On examination, signs of hirsutism were evident, but excessive acne or alopecia was not apparent. The patient's BMI was 24 kg/m2. Her endocrine profile showed increased serum levels of luteinizing hormone of 14.9 IU/l (upper limit of normal 10 U/l) and total testosterone 2.5 nmol/l (upper limit of normal in females 2.5 nmol/l). Levels of follicle-stimulating hormone and prolactin were normal. A subsequent transvaginal ultrasound scan confirmed bilateral polycystic ovaries; hence, the diagnosis of polycystic ovary syndrome (PCOS) was made according to current international consensus criteria.1 In addition, a 75 g oral glucose tolerance test indicated impaired glucose tolerance with a 2 h plasma glucose level of 8.5 mmol/l. Metformin treatment was, therefore, commenced at a dose of 850 mg twice daily to treat impaired glucose tolerance.
After confirmation of a normal semen analysis of the patient's husband and patency of the patient's Fallopian tubes, ovulation induction by use of clomifene was offered at a starting dose of 50 mg daily. Ovulation did not occur in the first cycle and so the dose was increased to 100 mg daily, but ovulation still failed to occur. Over the course of 8 months, the patient underwent five cycles of ovulation induction with gonadotropins, in which recombinant follicle-stimulating hormone was used at a starting dose of 50 U daily. Four of the five cycles produced a single preovulatory follicle and one cycle was abandoned because of multifollicular development. Despite confirmation of ovulation, the patient did not fall pregnant. At this stage the couple was offered in vitro fertilization (IVF) treatment.
The patient's first cycle of IVF treatment employed administration of gonadotropin-releasing-hormone (GnRH) agonist in a long protocol, with a low-dose stimulation regimen of gonadotropin starting at 112.5 U per day. The patient still continued to take metformin 850 mg twice daily throughout the cycle. Owing to the fact that no response occurred after 7 days of stimulation, the dose of gonadotropin was increased to 150 U per day. The response to this increased dose was good, and the patient was ready for egg collection after a further 5 days of stimulation. 10,000 U of human chorionic gonadotropin (hCG) was administrated intramuscularly to trigger ovulation. 16 eggs were collected from 20 follicles. The patient ultimately had two good-quality embryos replaced, but the subsequent pregnancy test result was negative.
The patient returned to the infertility unit 10 months afterwards to embark upon another cycle of IVF treatment using the same regimen as well as co-therapy with metformin. The starting dose of gonadotropins was 150 U daily. Unfortunately, after 7 days of stimulation, the patient's ovaries had over-responded, with 25 follicles <12 mm in diameter and nine follicles with diameters between 13 mm and 16 mm. The decision was made to reduce the dose of gonadotropins to 125 U and to freeze all created embryos with the aim to transfer them at a later date. The dose of hCG was halved to 5,000 U. 41 eggs were collected and 21 embryos were cryopreserved. The patient was given standard advice about ovarian hyperstimulation syndrome (OHSS) and the need to ensure adequate fluid intake.
2 days after the egg-collection procedure, the patient complained of increased abdominal swelling and pain, as well as vomiting. Clinical examination revealed considerable ascites and a distended abdomen. Ultrasonography showed bilateral enlarged ovaries; the largest ovarian diameter was 10 cm. The patient also showed hemoconcentration, with a white blood cell count of 31.7 
109/l, hemoglobin of 16.3 g/dl and hematocrit of 0.48. Her urea and electrolytes, liver-function test results and clotting parameters were all normal. The patient was admitted to hospital for observation and rehydration, initially with crystalloid fluid. A daily injection of enoxaparin 40 mg was also given as thrombus prophylaxis.
The patient's hourly urine output was poor, with a total positive fluid balance of 1,500 ml in 24 h. Infusion of concentrated 20% albumin followed by 4.5% albumin solutions was, therefore, commenced and had a beneficial effect in terms of urine output. However, the patient showed a continuous increase in abdominal distention over the next 12 h and she had worsening discomfort from abdominal swelling and shortness of breath. A chest radiograph revealed a left-sided pleural effusion (Figure 1).
A chest drain and an abdominal drain were inserted under ultrasonographic guidance. Over the following 24 h, 2 l of ascitic fluid and 1 l of pleuritic fluid were drained. Despite these measures, the patient's condition deteriorated, with oxygen saturation below 95% and arterial partial pressure of oxygen below 10 mmHg. The repeat chest radiograph revealed bilateral pleural effusion and pulmonary edema. An echocardiogram showed a minimal pericardial effusion with normal cardiac function. The patient was at risk of developing adult respiratory distress syndrome; she was, therefore, transferred to the high-dependence unit, which enabled intensive monitoring, insertion of a second chest drain and a central venous line. The patient's intravenous fluid regimen remained unchanged and the volume of albumin infusion was judged according to readings from the central venous line.
During the following 2 days, the patient's condition improved and all the drains were removed. She returned to the ward and was discharged 2 days after. The patient was followed up in the infertility unit for the next 2 weeks and no further complications were noted. She did not receive any further treatment and 18 months after IVF treatment, she became pregnant with the frozen embryos. She was discharged from the infertility unit after a viable pregnancy was confirmed at 8 weeks gestation by transvaginal ultrasound scan. The remaining frozen embryos are currently stored in the unit for her treatment in the future; consequently, she will not need to undergo another IVF cycle and her risk of developing OHSS again is negligible.
Discussion of diagnosis
PCOS is a common endocrine disorder. The condition affects 87% and 26% of women who attend gynecological endocrine clinics and present with a history of oligomenorrhea and amenorrhea, respectively.2, 3 PCOS is characterized by hyperandrogenism, menstrual disturbance and anovulatory infertility. Obesity often magnifies the clinical features of PCOS.3 Over the past 15 years, a large body of evidence has indicated that increased insulin resistance and compensatory hyperinsulinemia have key roles in the pathogenesis of PCOS.1, 3 The prevalence of PCOS depends on the diagnostic criteria used; the Rotterdam consensus criteria, published in 2004, suggest that the prevalence of this condition in the UK may be as high as 20%.3
Women with PCOS are often more insulin resistant and hyperinsulinemic than women without PCOS, matched for age and weight.3 Estimates indicate that 50% of women with PCOS are overweight.3 Furthermore, women with PCOS are prone to develop central obesity and this phenotype further exacerbates insulin resistance.2, 3 Hence, women with PCOS are at an increased risk of developing impaired glucose tolerance and type 2 diabetes mellitus.4 Additionally, women with PCOS who are of South Asian origin and live in the UK have greater insulin resistance and more severe symptoms than their white counterparts.2, 3 In this case, the patient had impaired glucose tolerance despite the fact that she was not obese.
Women suspected to have PCOS owing to their menstrual history and clinical signs of hyperandrogenism should undergo baseline, transvaginal ultrasonography to determine their ovarian morphology, as well as an assessment of their endocrine profile, as described in this case. Furthermore, an oral glucose tolerance test should be offered to obese women with PCOS to exclude impaired glucose tolerance or diabetes.
Treatment and management
The current first-line therapy for women with PCOS and obesity is weight loss through lifestyle modification and then ovulation-induction treatment with clomifene.5 Approximately 80% of anovulatory women with PCOS respond to clomifene treatment and the cumulative pregnancy rate after 6 months of treatment is between 40% and 50%. Ovulation induction therapy with gonadotropin is usually offered to patients who have failed to respond to clomifene. In addition, ovarian diathermy has been advocated by some clinicians as an effective alternative option.3
The initial Cochrane review on the treatment of PCOS showed that metformin improves the ovulation rate in women with this condition.6 Nevertheless, many of the studies included were small. A large, randomized, controlled study by Legro et al. published in 2007, which included more than 600 women, demonstrated that clomifene is far superior to metformin at inducing ovulation.7 In addition, use of metformin in conjunction with clomifene improves the rate of ovulation.6 Nonetheless, this benefit has not translated to an increased live birth rate in either normal weight8 or obese women with PCOS.7 More importantly, Legro et al. also demonstrated that obesity poses a statistically significant negative effect on live births in women with PCOS.7 Lifestyle modification is thus a key component for the improvement of reproductive function for overweight, anovulatory women with PCOS.5
Assisted-conception strategies are an effective therapy for infertility in women with PCOS who are refractory to standard ovulation induction or who have coexisting infertility factors.9 However, the response of women with PCOS to IVF treatment is often different from that of women with normal ovaries. Women with PCOS are more sensitive to stimulation with gonadotropins than are women with normal ovaries, as illustrated in this case. This increased sensitivity results in an increased number of eggs being collected, but these eggs have a reduced fertilization potential.9 Women with PCOS are, therefore, at increased risk of developing OHSS (Box 1), which is the most serious iatrogenic complication of IVF.10 In severe cases, which are uncommon (about 2% of all cases of OHSS), patients develop life-threatening conditions, such as hypovolemia, hemoconcentration, oligouria, electrolyte imbalance, liver dysfunction, thromboembolism, ascites, hydrothorax, pericardial effusion or even adult respiratory distress syndrome. The estimated mortality from OHSS is 1 per 30,000 cycles of IVF in the UK.10
The cardinal feature of the pathogenesis of OHSS is an increase in capillary permeability, which results in a shift of fluid from the intravascular system to the third compartment.10 Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen with potent angiogenic properties that is thought to be a key mediator of OHSS.10, 11 Serum and follicular levels of VEGF on the day of egg retrieval are elevated in patients with PCOS compared with controls and are also increased in women who develop OHSS.10, 13 Other risk factors for OHSS are young age, low body weight, previous OHSS and the use of hCG to trigger ovulation. Furthermore, OHSS is more likely to occur during a pregnancy cycle than a nonpregant cycle because endogenous production of hCG takes place, which further enhances the secretion of VEGF from granulosa cells.12
The preventative measures for OHSS during IVF treatment include employing a low-dose, step-up stimulation regime, reducing the dose of hCG, using GnRH agonist to trigger ovulation in a GnRH antagonist IVF cycle, coasting (withholding gonadotropins while continuing pituitary suppression), prophylactic albumin infusion, elective embryo freezing or cycle cancellation.10 Furthermore, cotherapy with metformin during IVF treatment reduces OHSS risk in women with PCOS.13 This finding was also supported by a meta-analysis published in 2006 that showed a reduced risk of OHSS with metformin coadministration (odds ratio 0.21, 95% CI 0.11–0.41).14
Agrawal et al. demonstrated that insulin augmented the effects of gonadotropin and hCG on the production of VEGF from human luteinized granulosa cells, which result in the higher serum VEGF levels observed in women with PCOS compared with women with normal ovaries.11 These findings are in agreement with the results of an in vitro study on the effects of insulin and insulin-like growth factor I on VEGF production by human luteinized granulosa cells; the study showed that cells from women with and without PCOS responded differently.15 On the basis of this evidence, the benefit of metformin therapy during IVF may be attributed to the drug's effect of reducing insulin levels and thereby reducing subsequent production of VEGF. Nonetheless, despite all the preventative measures available, women with PCOS are still at risk of developing OHSS during IVF treatment, as illustrated in the case described.
OHSS can be a progressive condition. Patients with symptoms that suggest severe OHSS should, therefore, be hospitalized for close monitoring of vital signs (including fluid balance) and should receive appropriate supportive care. Details of the management of OHSS were reported in a 2008 review.10 A multidisciplinary team approach involving critical-care specialists is mandatory when the condition of the patient continues to deteriorate.
Conclusions
PCOS is a common condition. Although increased insulin resistance has a key role in its pathogenesis, use of insulin-lowering or insulin-sensitizing agents might not improve patients' reproductive outcomes, particularly in women who are obese. Lifestyle modification programs should be integrated into the health-care pathway. Patients with PCOS are at increased risk of over-responding to stimulation with gonadotropins compared with women who have normal ovaries. Hence, frequent monitoring of the ovarian response to stimulation by ultrasonography coupled with a low-dose stimulation regimen is pivotal in the management of women with PCOS who are undergoing fertility treatment. OHSS is a serious, potentially life-threatening condition. Early supportive interventions in conjunction with a specialist team can reduce the morbidity of OHSS.
