Consensus on infertility treatment related to polycystic ovary syndrome

Ovarian hyperstimulation syndrome (OHSS) is a rare iatrogenic complication of ovarian stimulation occurring during the luteal phase or during early pregnancy. Fortunately, the reported prevalence of the severe form of OHSS is small, ranging from 0.5 to 5%. Nevertheless, as this is an iatrogenic complication of a non-vital treatment with a potentially fatal outcome, the syndrome remains a serious problem for specialists dealing with infertility. The aim of this literature review was to determine whether it is possible to identify patients at risk, and which preventive method should be applied when an exaggerated ovarian response occurs. Data pertaining to the epidemiology and prevention of OHSS in women were searched using Medline, Current Contents and PubMed, and are summarized. Preventive strategies attempt either to limit the dose or concentration of hCG or to find a way to induce luteolysis without inducing a detrimental effect on endometrial and oocyte quality. The following particular preventive strategies were reviewed: cancelling the cycle; coasting; early unilateral ovarian follicular aspiration (EUFA); modifying the methods of ovulation triggering; administration of glucocorticoids, macromolecules and progesterone; cryopreservation of all embryos; and electrocautery or laser vaporization of one or both ovaries.

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Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review

Background
Advances in cell culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage stage embryo transfer to blastocyst stage transfer. The rationale for blastocyst transfer is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos, thus resulting in better live birth rates.

Objectives
To determine whether blastocyst stage (day 5 to 6) embryo transfers improve the live birth rate, and other associated outcomes, compared with cleavage stage (day 2 to 3) embryo transfers.

Search methods
We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2016, Issue 4), MEDLINE, EMBASE, PsycINFO, CINAHL, and Bio extracts from inception to 4th April 2016. We also searched registers of ongoing trials and the reference lists of studies retrieved.

Selection criteria
We included randomised controlled trials (RCTs) which compared the effectiveness of blastocyst versus cleavage stage transfers.

Data collection and analysis
We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth and cumulative clinical pregnancy rates. Secondary outcomes were clinical pregnancy, multiple pregnancy, high order pregnancy, miscarriage, failure to transfer embryos, and embryo freezing. We assessed the overall quality of the evidence for the main comparisons using GRADE methods.

Main results
We included 27 RCTs (4031 couples or women).

The live birth rate following fresh transfer was higher in the blastocyst transfer group (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.20 to 1.82; 13 RCTs, 1630 women, I2 = 45%, low quality evidence) following fresh transfer. This suggests that if 29% of women achieve live birth after fresh cleavage stage transfer, between 32% and 42% would do so after fresh blastocyst stage transfer.

There was no evidence of a difference between the groups in rates per couple of cumulative pregnancy following fresh and frozen-thawed transfer after one oocyte retrieval (OR 0.89, 95% CI 0.64 to 1.22; 5 RCTs, 632 women, I2 = 71%, very low quality evidence).

The clinical pregnancy rate was also higher in the blastocyst transfer group, following fresh transfer (OR 1.30, 95% CI 1.14 to 1.47; 27 RCTs, 4031 women, I2 = 56%, moderate quality evidence). This suggests that if 36% of women achieve clinical pregnancy after fresh cleavage stage transfer, between 39% and 46% would do so after fresh blastocyst stage transfer.

There was no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; 19 RCTs, 3019 women, I2 = 30%, low quality evidence), or miscarriage (OR 1.15, 95% CI 0.88 to 1.50; 18 RCTs, 2917 women, I2 = 0%, low quality evidence). These data are incomplete as under 70% of studies reported these outcomes.

Embryo freezing rates were lower in the blastocyst transfer group (OR 0.48, 95% CI 0.40 to 0.57; 14 RCTs, 2292 women, I2 = 84%, low quality evidence). This suggests that if 60% of women have embryos frozen after cleavage stage transfer, between 37% and 46% would do so after blastocyst stage transfer. Failure to transfer any embryos was higher in the blastocyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; 17 RCTs, 2577 women, I2 = 36%, moderate quality evidence). This suggests that if 1% of women have no embryos transferred in (planned) fresh cleavage stage transfer, between 2% and 4% will have no embryos transferred in (planned) fresh blastocyst stage transfer.

The evidence was of low quality for most outcomes. The main limitation was serious risk of bias, associated with failure to describe acceptable methods of randomisation, and unclear or high risk of attrition bias.

Authors' conclusions
There is low quality evidence for live birth and moderate quality evidence for clinical pregnancy that fresh blastocyst stage transfer is associated with higher rates than fresh cleavage stage transfer. There was no evidence of a difference between the groups in cumulative pregnancy rates derived from fresh and frozen-thawed cycles following a single oocyte retrieval, but the evidence for this outcome was very low quality. Thus, although there is a benefit favouring blastocyst transfer in fresh cycles, it remains unclear whether the day of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage to enable couples or women undergoing assisted reproductive technology (ART) and service providers to make well informed decisions on the best treatment option available.

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Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. The clinical manifestation of PCOS varies from a mild menstrual disorder to severe disturbance of reproductive and metabolic functions. Management of women with PCOS depends on the symptoms. These could be ovulatory dysfunction-related infertility, menstrual disorders, or androgen-related symptoms. Weight loss improves the endocrine profile and increases the likelihood of ovulation and pregnancy. Normalization of menstrual cycles and ovulation could occur with modest weight loss as little as 5% of the initial weight. The treatment of obesity includes modifications in lifestyle (diet and exercise) and medical and surgical treatment. In PCOS, anovulation relates to low follicle-stimulating hormone concentrations and the arrest of antral follicle growth in the final stages of maturation. This can be treated with medications such as clomiphene citrate, tamoxifen, aromatase inhibitors, metformin, glucocorticoids, or gonadotropins or surgically by laparoscopic ovarian drilling. In vitro fertilization will remain the last option to achieve pregnancy when others fail. Chronic anovulation over a long period of time is also associated with an increased risk of endometrial hyperplasia and carcinoma, which should be seriously investigated and treated. There are androgenic symptoms that will vary from patient to patient, such as hirsutism, acne, and/or alopecia. These are troublesome presentations to the patients and require adequate treatment. Alternative medicine has been emerging as one of the commonly practiced medicines for different health problems, including PCOS. This review underlines the contribution to the treatment of different symptoms.

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Treatment options for polycystic ovary syndrome.

The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.

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Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?

Sixteen patients with polycystic ovarian syndrome (PCO) were treated by in-vitro fertilization (26 treatment cycles). The results were compared with 37 normo-ovulatory women with tubal disease (37 treatment cycles). The oestradiol and progesterone levels were higher during the follicular phase in the PCO patients, but were statistically significantly higher only on the day after human chorionic gonadotrophin administration. Although more oocytes were recovered per cycle from the PCO group (19.3 +/- 6.1) than from the control group (5.4 +/- 2.9) with P less than 0.004, the mean numbers of embryos per cycle were similar in both groups (3.7 +/- 2.4 versus 3.6 +/- 2.2, respectively). The pregnancy rate was also comparable in both groups (30.7 versus 29.7%, respectively). The fact that more oocytes are recovered from PCO patients, balances their lower fertilization and cleavage rates. We conclude, therefore, that IVF treatment may be a viable solution for PCO patients resistant to an in-vivo protocol treatment regimes.

The treatment of patients with polycystic ovarian syndrome by in-vitro fertilization and embryo transfer: a comparison of results with those of patients with tubal infertility

results: One hundred and twenty-five women after ovum donation aged � 40 were studied. Of those, 42 women carried twin pregnancies and 83 carried singletons. The 42 women carrying twins comprised the study group and were compared with 417 control women with twins. Mean maternal age was 49.2+ 4.3 years. Hypertensive complications (50%), diabetes in pregnancy (31%) and hospitalization in pregnancy (69%) were all extremely high in the study group. Mean gestational age at delivery was lower for the study group compared with controls (35.2+ 2.3 versus 35.7+ 2.6 weeks), with 35.7% of infants in the study group born � 34 weeks gestation compared with 21.8% of controls, (OR: 1.99, 95% CI: 1.02–3.89). Mean birthweight was also significantly lower for study group infants compared with controls, with 77% of study infants born ,2500 g compared with only 60% of controls (OR: 2.22, 95% CI: 1.3 –3.77). conclusions: Pregnancy in advanced maternal age women after ovum donation carrying twins is associated with significant maternal and fetal complications, with increased risks of prematurity and lower birthweight. Possibly, the aged uterus is less suitable for carrying a multifetal pregnancy than a younger uterus. Therefore, the alternative of transferring a single, good-quality embryo should be the preferred option.

The aged uterus: multifetal pregnancy outcome after ovum donation in older women

STUDY QUESTION: Does the position of the germinal vesicle (GV) in human oocytes correlate with molecular and morphological parameters as well as with maturation-competence? SUMMARY ANSWER: The position of GV in human oocytes correlates with density of microtubule (MT) filaments, concentration of Fyn, nucleolus localization and the ability of the oocytes to complete maturation following GV breakdown (GVBD). WHAT IS KNOWN ALREADY: Our knowledge is confined to oocytes of young mice where maturation-competence is correlated with a central GV and regulated by MTs and the presence of a chromatin ring. Fyn kinase is localized at the spindle and cortex of mouse oocytes and plays a role in both maturation and MT stabilization. STUDY DESIGN, SIZE, DURATION: Spatial localization of the GV and nucleolus (central or peripheral), the presence of a chromatin ring, the localization of Fyn, MT density and oocyte maturation were assessed in 153 human oocytes, 335 oocytes from young mice (2-month-old) and 146 oocytes from old mice (12-month-old). PARTICIPANTS/MATERIALS, SETTING, METHODS: GV human oocytes were donated by consenting female patients (n = 57), 21-45-year-old undergoing IVF/ICSI. As a control, GV mouse oocytes were collected from female mice after injection of pregnant mares' serum gonadotrophin. Human and mouse GV oocytes allocated for immunocytochemistry were fixed on day of retrieval, stained with specific antibodies and imaged using a confocal laser-scanning microscope. Human and mouse oocytes allocated for maturation were incubated for 48 and 24 h, respectively. GVBD and extrusion of the first polar body (PBI) were assessed using differential interference contrast optics. MAIN RESULTS AND THE ROLE OF CHANCE: GV location was peripheral and independent of age in 69.9% of the human oocytes, but GV location did vary with age in mice oocytes; it was central in 89.9% of the oocytes retrieved from young-mice and peripheral in 52.1% of the oocytes retrieved from old mice (P < 0.05). A central GV, whether in human or mouse oocytes, was highly correlated with a central nucleolus, absence of Fyn at the GV and a dense MT network (P < 0.05), whereas a peripheral GV correlated with peripheral nucleolus, presence of Fyn at the GV and a flimsy MT network. After 48 h in culture, no degeneration was observed in human central-GV oocytes, however, 12/95 (12.6%) of the peripheral-GV oocytes degenerated (P < 0.05). No correlation was observed between GV position and presence of a chromatin ring. The percentage of human oocytes that extruded the PBI after completing GVBD was significantly higher (73.7%) in central than in peripheral-GV oocytes (45.8%; P < 0.05). In mice oocytes, central location of the GV correlated with maturation competence in young (P < 0.05) but not old mice. LIMITATIONS, REASONS FOR CAUTION: The fact that the human GV oocytes used in this study were exposed to gonadotrophic stimulation but failed to mature in vivo might be a sign of their low quality and this should be considered when drawing conclusions from the data. Furthermore, our observation that only peripheral-GV human oocytes were degraded may indicate that they are of a lower quality than central-GV human oocytes. WIDER IMPLICATIONS OF THE FINDINGS: We suggest that the central location of GV within the oocytes, which is associated with an absence of Fyn at the GV and the presence of thick filamentous MTs in the ooplasm, may serve as a predictor of successful maturation and provide new insights for the use of IVM.

Morphological and molecular markers are correlated with maturation-competence of human oocytes

Summary

Basic semen analysis is insufficient for determining the fertility potential. The aim of this study was to determine if hyperactivated motility (HAM) and acrosome reaction (AR) can be useful tests for evaluating semen quality during male infertility evaluations and to help the clinician decide whether regular insemination or intracytoplasmic sperm injection (ICSI) is preferable during in vitro fertilisation. A prospective study was conducted. Patients with normal sperm according to World Health Organization guidelines who underwent IVF treatment and planned regular insemination were asked to participate. A portion of sperm sample was evaluated for HAM and AR on day of ovum pick up. In HAM assessment, 93.3% of patients with increased HAM had a high fertilisation rate compared with 64% in the group without increased HAM (P = 0.059). For the AR evaluation, 91.7% of samples with a low rate of spontaneous AR had a high fertilisation rate compared with 39.3% in the group with a high rate of spontaneous AR (P = 0.004).

Assessment of sperm hyperactivated motility and acrosome reaction can discriminate the use of spermatozoa for conventional in vitro fertilisation or intracytoplasmic sperm injection: Preliminary results

A. Shulman

Papers

The treatment of patients with polycystic ovarian syndrome by in-vitro fertilization and embryo transfer: a comparison of results with those of patients with tubal infertility

The aged uterus: multifetal pregnancy outcome after ovum donation in older women

Morphological and molecular markers are correlated with maturation-competence of human oocytes

Assessment of sperm hyperactivated motility and acrosome reaction can discriminate the use of spermatozoa for conventional in vitro fertilisation or intracytoplasmic sperm injection: Preliminary results

Ectopic pregnancy and laparoscopy: review of 1197 patients treated by salpingectomy or salpingotomy