et al. Echocardiography and monitoring patients receiving dopamine agonist therapy for hyperprolactinaemia: A joint position statement of the British Society of Echocardiography, the British Heart Valve Society and the Society for Endocrinology. Clin Endocrinol (Oxf) 2019; 90:662–9.27 27 Ioachimescu AG, Fleseriu M, Hoffman AR, et al. Psychological effects of dopamine agonist treatment in patients with hyperprolactinemia and prolactin‐secreting adenomas. Eur J Endocrinol 2019; 180:31–40.
28 28 Konopka P, Raymond JP, Merceron RE, et al. Continuous administration of bromocriptine in the prevention of neurological complications in pregnant women with prolactinomas. Am J Obstet Gynecol 1983; 146:935–8.
29 29 Krupp P, Monka C. Bromocriptine in pregnancy: safety aspects. Klin Wochenschr 1987; 65:823–7.
15 The patient with polycystic ovaries
Adam H. Balen
Leeds Fertility, Leeds, UK
Case History 1: A 28‐year‐old woman attends to commence a cycle of ICSI because her partner has severe oligospermia. She is healthy, with a regular menstrual cycle, a normal body weight and no clinical stigmata of PCOS. Her baseline endocrine profile is normal. On a baseline ultrasound scan she is found to have polycystic ovaries.
Case History 2: A 29‐year‐old woman with classical PCOS attends to commence a cycle of IVF. She has oligomenorrhea, hirsutism, a BMI of 28, a normal total testosterone and polycystic ovaries on ultrasound scan. She has already undergone ovulation induction with clomiphene citrate but did not ovulate. Subsequent treatment with low dose step‐up gonadotropin therapy achieved ovulation but no pregnancy after six cycles of treatment, hence the plan for IVF.
Background
Women with anovulatory infertility secondary to polycystic ovary syndrome (PCOS) should first be treated by ovulation induction and only then proceed to IVF if a pregnancy does not result despite repeated ovulation. IVF is considered as the third‐line management for PCOS when first‐ and second‐line agents have not been successful in achieving a pregnancy or when there are additional causes of infertility such as pathology of the fallopian tubes or sperm abnormalities in the woman’s partner. The presence of polycystic ovaries is a major risk factor for developing ovarian hyperstimulation syndrome (OHSS) and so care is required when planning the stimulation regimen. The morphological appearance of polycystic ovaries may come to light for the first time at a baseline ultrasound scan, as not all women with polycystic ovaries have symptoms of the polycystic ovary syndrome. Indeed between 20–30% of women appear to have polycystic ovaries [1,2].
PCOS is a heterogeneous condition whose pathophysiology appears to be multifactorial and polygenic. The definition of the syndrome has been much debated. Key features include menstrual cycle disturbance, hyperandrogenism and obesity. There are many extra‐ovarian aspects to the pathophysiology of PCOS, yet ovarian dysfunction is central. The Rotterdam international consensus definition of the PCOS has stood the test of time and is the presence of two out of the following three criteria: (1) menstrual cycle disturbance (oligo‐ and/or anovulation); (2) hyperandrogenism (clinical and/or biochemical); (3) polycystic ovaries, with the exclusion of other causes of menstrual disturbance or androgen excess [1,2]. Using modern, high resolution ultrasound technology, the consensus for the morphology of the polycystic ovary has been defined as an ovary with 20 or more follicles measuring 2–9 mm in diameter and/or increased ovarian volume (>10 cm3) [2].
The response of the polycystic ovary to ovulation induction aimed at the development of unifollicular ovulation is well documented and differs significantly from that of normal ovaries. The response tends to be slow initially, with a significant risk of ovarian hyperstimulation once recruitment has started and so there are significant challenges in achieving safe ovulation induction [3]. The response of the polycystic ovary in the context of an IVF program also differs from the normal, whether the patient has the full syndrome or not. Indeed, a number of studies have shown that significantly more oocytes are recovered per cycle in women with polycystic ovaries compared with normal ovaries. Despite the fact that they often require a lower total dose of gonadotropin during stimulation compared with women with normal ovaries, women with PCOS are at a greater risk of developing moderate to severe OHSS.
It is difficult to know the true rate of OHSS, as studies vary considerably with an estimated prevalence of 20% to 33% in its mild form and 3% to 8% in its moderate or severe form, and possibly even higher for women with polycystic ovaries [4]. A 2019 meta‐analysis [5] aimed to study whether pregnancy‐related outcomes and complications differed between patients with PCOS and those with other causes of infertility who had undergone IVF. Women with PCOS had higher risks of miscarriage (OR 1.41, 95% CI 1.04–1.91), OHSS (OR 4.96, 95% CI 3.73–6.60), gestational diabetes mellitus (OR 2.67, 95% CI 1.43–4.98), pregnancy‐induced hypertension (OR 2.06, 95% CI 1.45–2.91), preterm birth (OR 1.60, 95% CI 1.25–2.04) and large‐for‐gestational‐age babies (OR 2.10, 95% CI 1.01–4.37). On the other hand, they had similar rates of clinical pregnancy, multiple pregnancy, small for gestational age and congenital malformations, and a higher live birth rate. So when preparing women with PCOS for IVF treatments, it is important to remember that they are at increased risk of adverse pregnancy‐related outcomes, which may be related to higher rates of obesity and metabolic disturbance; and so enhancing preconception health is essential before commencing treatment.
Another consequence of obesity among women with PCOS is an increased requirement for FSH stimulation. Therefore, they may not respond to a low dose stimulation regimen. However, once the dose of FSH is increased and the threshold reached, the subsequent response can be explosive, with an increasing risk of OHSS. There are several possible explanations for the excessive response to ovarian stimulation. Women with PCOS have an increased cohort of antral follicles due to an increase in recruitment of primordial follicles from the resting pool, which are sensitive to exogenous gonadotropins. The increased number of antral follicles is also reflected by elevation of anti‐Müllerian hormone (AMH) levels in women with PCOS compared with those with normal ovaries.
Management options
All patients undergoing ovarian stimulation, whether to correct anovulation or for assisted reproduction techniques (ART), should of course have a pretreatment ultrasound scan and if polycystic ovaries are detected the dose of gonadotropin lowered (to a starting dose of no more than 50–150 IU depending upon age and other factors).
OHSS is usually associated with the presence of a large number of small to moderate sized follicles (< 14 mm diameter) rather than larger, more mature follicles. When serum estradiol concentrations are 10,000–15,000 pmol/L with 20–30 follicles, the patient is at risk of OHSS. A decision then has to be taken as to whether or not to proceed with oocyte retrieval and then potentially electively cryopreserve any embryos created or decide if it is safe to perform a fresh embryo transfer, with the inherent increased risk of late‐onset and prolonged OHSS. If the serum estradiol concentration becomes greater than 15,000 pmol/L (5,000 pg/ml) with more than 30–40 follicles, the treatment cycle should be canceled.
The long GnRH agonist protocol
Historically a “long” protocol with pituitary desensitization using a GnRH agonist was used although this has now largely been replaced by the GnRH antagonist protocols in women with PCOS. If a long protocol of GnRH agonist treatment is followed by treatment with one of the “pure” or recombinant FSH preparations, one must also be aware that the lack of LH changes the usual relationship of follicle number to circulating estradiol levels. In this situation measurement of serum estradiol concentrations underestimates
