Miro Kasum

Thrombosis following ovarian hyperstimulation syndrome

Abstract The aim of this review is to analyse the pathophysiology and complications of thrombosis in conjuction with ovarian hyperstimulation syndrome (OHSS) following ovulation induction and to suggest practical guidelines usefull for the prevention and treatment. Although the incidence of thrombosis varies from 0.2% among in vitro fertilization (IVF) cycles and up to 10% for severe cases of the syndrome, it represents the most dangerous complication of OHSS. Different changes in haemostatic markers have been found to create a state of hypercoagulability, but no single standard test is available to estimate the state of thrombosis. The role of markers for thrombophilia is controversial. Thromboses are mostly venous (67–75%) involving upper limbs and neck, then arterial (25–33%) which are mainly intracerebral. The predominant sites of venous thromboembolism in the upper part of the body may be explained by higher concentrations of estrogens drained through lymphatic ducts from ascites and by compression of rudimentary branchyal cysts. Once early diagnosis is established, it is crucial to use an anticoagulant treatment with heparin proceeded with thromboprophylaxis. However, identification of patients at risk and preventive measures of OHSS are the best means in reducing the risk of thrombosis after ovarian stimulation. Chinese abstract 本综述的目的是分析促排卵导致的卵巢过度刺激综合征（OHSS）并发血栓形成的病理生理学特征与并发症，并针对其预防与治疗提出实用的临床指南。虽然体外受精治疗中血栓形成的发生率介于0.2∼10%之间，它却是OHSS最危险的并发症。现已发现了多种造成高凝状态的凝血标志物，但还没有单一的检验标准用于评估血栓形成的状态。关于标志物在血栓形成倾向中所起的的作用存在争议。血栓多为静脉血栓（67∼75%），包括上肢与颈部；而动脉血栓（25∼33%）多位于大脑内部。静脉血栓多位于身体上部，可能是由于腹水中较高浓度的雌激素经淋巴管排出，及残留囊肿的加压作用。一旦早期诊断确立，重要的是应用抗凝血剂治疗及肝素预防血栓。但是，鉴定高危患者与预防OHSS的发生是降低卵巢刺激后血栓风险的最好办法。

Macroprolactinemia: new insights in hyperprolactinemia

Hypersecretion of prolactin by lactotroph cells of the anterior pituitary may lead to hyperprolactinemia in physiological, pathological and idiopathic conditions. Most patients with idiopathic hyperprolactinemia may have radiologically undetected microprolactinomas, but some may present other causes of hyperprolactinemia described as macroprolactinemia. This condition corresponds to the predominance of higher molecular mass prolactin forms (big-big prolactin, MW > 150 kDa), that have been postulated to represent prolactin monomer complexed with anti-prolactin immunoglobulins or autoantibodies. The prevalence of macroprolactinemia in hyperprolactinemic populations between 15–46% has been reported. In the pathophysiology of macroprolactinemia it seems that pituitary prolactin has antigenicity, leading to the production of anti-prolactin autoantibodies, and these antibodies reduce prolactin bioactivity and delay prolactin clearance. Antibody-bound prolactin is big enough to be confined to vascular spaces, and therefore macroprolactinemia develops due to the delayed clearance of prolactin rather than increased production. Although the clinical symptoms are less frequent in macroprolactinemic patients, they could not be diff erentiated from true hyperprolactinemic patients, on the basis of clinical features alone. Although gel filtration chromatography (GFC) is known to be the gold standard for detecting macroprolactin, the polyethylene glycol precipitation (PEG) method has off ered a simple, cheap, and highly suitable alternative. In conclusion, macroprolactinemia can be considered a benign condition with low incidence of clinical symptoms and therefore hormonal and imaging investigations as well as medical or surgical treatment and prolonged follow-up are not necessary.

Dopamine agonists in prevention of ovarian hyperstimulation syndrome

Abstract The aim of this review is to analyze the efficacy of different dopamine agonists in the prevention of ovarian hyperstimulation syndrome (OHSS). Cabergoline, quinagolide and bromocriptine are the most common dopamine agonists used. There are wide clinical variations among the trials in the starting time (from the day of human chorionic gonadotrophin (hCG) to the day following oocyte retrieval); the duration of the treatment (4–21 days), the dose of cabergoline (0.5 mg or 0.25 mg orally) and in the regimens used. At present, the best known effective regimen is 0.5 mg of cabergoline for 8 days or rectal bromocriptine at a daily dose of 2.5 mg for 16 days. Dopamine agonists have shown significant evidences of their efficacy in the prevention of moderate and early-onset OHSS (9.41%), compared with a placebo (21.45%), which cannot be confirmed for the treatment of late OHSS. It would be advisable to start with the treatment on the day of hCG injection or preferably a few hours earlier. The use of dopamine agonists should be indicated in patients at high risk of OHSS, as well as in patients with a history of previous OHSS even without evident signs of the syndrome. Chinese abstract 这篇综述的目的是分析不同的多巴胺受体激动剂在预防卵巢过度刺激综合征（OHSS）中的疗效。卡麦角林，喹高利特和溴隐亭是最常见的多巴胺受体激动剂。在本研究的开始阶段，卡麦角林的使用时间（从HCG日至取卵日4天-21天不等），使用剂量（0.5mg或0.25mg口服）和使用方案等临床因素变化很大。目前，最有效的方案是卡麦角林每天0.5mg口服8天，或者直肠给药0.25mg每天，使用16天。多巴胺受体激动剂有显著地预防中度和早发性卵巢过度刺激综合征(9.41%)的疗效，与对照组（21.45%）相比较，发病率显著降低，但是其治疗晚期OHSS的效果尚不确定。目前，多建议在HCG注射的当日开始使用，提前几个小时效果可能更好。多巴胺受体激动剂应当对具有高OHSS发生风险的患者以及之前有OHSS史,甚至没有发病迹象的患者也可以使用。

Assessment of ovarian reserve after unilateral diathermy with thermal doses adjusted to ovarian volume

Abstract Women with polycystic ovary syndrome seem to have a larger ovarian reserve. However, regardless of a greater reserve, diminished ovarian reserve has been reported after laparoscopic diathermy. The aim of this article was to determine whether the doses adjusted unilateral laparoscopic ovarian drilling with diathermy (ULOD) diminishes ovarian reserve to compare with bilateral laparoscopic ovarian drilling with diathermy (BLOD). Ninety-six women were assigned in two groups. One group underwent ULOD receiving thermal doses (0–840 J per ovary) adjusted to volume one ovary. The other group underwent BLOD receiving fixed doses (600 J per ovary). Ovarian reserve markers [anti-Müllerian hormone (AMH); antral follicle count (AFC) and ovarian volume] were measured before and after surgery (1 and 6 months). Both groups showed a decrease in AMH after surgery, but it was significantly more distinct in the BLOD versus ULOD group (2.0 ng/mL versus 1.3 ng/mL; p = 0.018) in the first follow-up month and remained significantly different through the sixth follow-up month (1.9 ng/mL versus 1.15 ng/mL; p = 0.023). In contrast, in the sixth month, the ULOD versus BLOD showed a significantly greater increase AFC (p < 0.001) and volume (p = 0.013). Our findings evidenced that the dose-adjusted unilateral diathermy (60 J/cm3) does not have significant and long-term effects on ovarian reserve. Chinese abstract 患有多囊卵巢综合征的妇女似乎具有更多的卵巢储备，然而也有腹腔镜透热打孔术后卵巢储备功能降低的报道。本篇文章的目的为探究与双侧腹腔镜下卵巢打孔术(BLOD)相比，调整透热剂量单侧腹腔镜下卵巢打孔术(ULOD)对卵巢储备降低是否有影响。96名妇女被分为两组，一组接受了根据其一侧卵巢体积所调整透热剂量的ULOD（0-840J每卵巢），另一组接受了固定透热剂量的BLOD（600J每卵巢）。在术前和术后（1个月及6个月）均测定了卵巢储备指标[抗苗勒氏管激素（AMH）；窦卵泡计数（AFC）和卵巢体积] 。两组在术后都出现了AMH的降低，但在术后一个月BLOD组相较于ULOD组表现得更为明显（2.0ng/mL 比1.3ng/mL; p=0.018），术后六个月这种明显的区别仍然存在（1.9 ng/mL 比1.15 ng/mL; p=0.023）。与此相比，在第六个月ULOD组AFC与卵巢体积升高的幅度与BLOD组相比显著增多。研究结果表明根据卵巢体积调整剂量的单侧卵巢透热疗法(60 J/cm3)对卵巢储备功能无显著和长期的影响。

Macrophages and Leydig cells in testicular biopsies of azoospermic men.

A number of studies have indicated that testicular macrophages play an important role in regulating steroidogenesis of Leydig cells and maintain homeostasis within the testis. The current paper deals with macrophages (CD68 positive cells) and Leydig cells in patients with nonobstructive azoospermia (NOA). Methods employed included histological analysis on semi- and ultrathin sections, immunohistochemistry, morphometry, and hormone analysis in the blood serum. Histological analysis pointed out certain structural changes of macrophages and Leydig cells in NOA group of patients when compared to controls. In the testis interstitium, an increased presence of CD68 positive cells has been noted. Leydig cells in NOA patients displayed a kind of a mosaic picture across the same bioptic sample: both normal and damaged Leydig cells with pronounced vacuolisation and various intensity of expression of testosterone have been observed. Stereological analysis indicated a significant increase in volume density of both CD68 positive and vacuolated Leydig cells and a positive correlation between the volume densities of these cell types. The continuous gonadotropin overstimulation of Leydig cells, together with a negative paracrine action of macrophages, could result in the damage of steroidogenesis and deficit of testosterone in situ.

Fertility preservation options in breast cancer patients

Abstract The purpose of this review is to analyse current options for fertility preservation in young women with breast cancer (BC). Considering an increasing number of BC survivors, owing to improvements in cancer treatment and delaying of childbearing, fertility preservation appears to be an important issue. Current fertility preservation options in BC survivors range from well-established standard techniques to experimental or investigational interventions. Among the standard options, random-start ovarian stimulation protocol represents a new technique, which significantly decreases the total time of the in vitro fertilisation cycle. However, in patients with oestrogen-sensitive tumours, stimulation protocols using aromatase inhibitors are currently preferred over tamoxifen regimens. Cryopreservation of embryos and oocytes are nowadays deemed the most successful techniques for fertility preservation in BC patients. GnRH agonists during chemotherapy represent an experimental method for fertility preservation due to conflicting long-term outcome results regarding its safety and efficacy. Cryopreservation of ovarian tissue, in vitro maturation of immature oocytes and other strategies are considered experimental and should only be offered within the context of a clinical trial. An early pretreatment referral to reproductive endocrinologists and oncologists should be suggested to young BC women at risk of infertility, concerning the risks and benefits of fertility preservation options. Chinese abstract 本文旨在分析目前针对年轻乳腺癌患者生殖力保护的选择方法。由于癌症治疗技术的进步及延迟生育，越来越多的乳腺癌似乎应将其生殖力保护视为一项重要的问题。目前乳腺癌幸存者生殖力保护的选择范围囊括了完善的标准技术及实验性或临床性干预研究。标准方法中，随机启动卵巢刺激方案作为一项新技术可显著降低体外受精周期的总体时长。然而，目前对于雌激素敏感的肿瘤患者，使用芳香化酶抑制剂刺激方案优于接受他莫昔芬治疗。胚胎和卵母细胞冻存被认为是当今乳腺癌患者生殖力保护最成功的技术。由于应用GnRH激动剂的远期疗效尚存争议，且考虑其安全性和有效性，目前将化疗期间应用GnRH激动剂视为患者生殖力保护的实验性方法。卵巢组织冻存、卵母细胞体外成熟技术及其他技术都处于实验性阶段，且仅处于临床试验范围内。对于存在不孕不育风险的年轻乳腺癌患者，在权衡生殖力保护方法利弊后，应给予早期及时转至生殖内分泌专家和肿瘤学专家进行诊治。

Fertility preservation with ovarian stimulation protocols prior to cancer treatment

Abstract: An increasing trend towards later childbearing has been reported recently in many developed countries. Although the incidence of reproductive age in women who have delayed pregnancy with cancer is 10%, they may be concerned regarding the preservation of ovarian function due to advanced fertile age and with the impact of cancer treatment on later fertility. Among multiple strategies controlled, ovarian stimulation for embryo or oocyte cryopreservation is currently the most established method for fertility preservation. It is important to choose the appropriate ovulation induction protocol prior to oncologic treatment, because most of these patients have only the chance of a single cycle to conceive. Current treatment protocols offer a minimal time delay until oncologic treatment is commenced. In urgent settings, random-start ovarian stimulation represents a new technique which provides a significant advantage by decreasing the total time of the treatment, because it may be started irrespective of the phase of the cycle without compromising oocyte yield and maturity before cancer treatment. However, in patients with oestrogen-sensitive cancers stimulation, protocols using letrozole are currently preferred over tamoxifen regimens, and therefore, it may be highly advisable to use letrozole with gonadotrophins routinely as a safe, effective and novel protocol of ovulation induction.

Combined ovulation triggering with GnRH agonist and hCG in IVF patients

Abstract The aim of the review is to analyse the combination of a gonadotrophin releasing hormone (GnRH) agonist with a human chorionic gonadotrophin (hCG) trigger, for final oocyte maturation in in vitro fertilisation (IVF) cycles. The concept being a ‘‘dual trigger’’ combines a single dose of the GnRH agonist with a reduced or standard dosage of hCG at the time of triggering. The use of a GnRH agonist with a reduced dose of hCG in high responders demonstrated luteal phase support with improved pregnancy rates, similar to those after conventional hCG and a low risk of ovarian hyperstimulation syndrome (OHSS). The administration of a GnRH agonist and a standard hCG in normal responders, demonstrated significantly improved live-birth rates and a higher number of embryos of excellent quality, or cryopreserved embryos. The concept of the ‘‘double trigger” represents a combination of a GnRH agonist and a standard hCG, when used 40 and 34 h prior to ovum pick-up, respectively. The use of the ‘‘double trigger” has been successfully offered in the treatment of empty follicle syndrome and in patients with a history of immature oocytes retrieved or with low/poor oocytes yield. Further prospective studies are required to confirm the aforementioned observations prior to clinical implementation.

Follicular progesterone elevations with ovulation induction for IVF.

Abstract The purpose of this review is to analyse the sources and effects of follicular progesterone elevations during ovarian stimulation, with the underlying mechanisms and preventive strategies on the in vitro fertilisation pregnancy outcome. In the early follicular phase, a flare-up effect of gonadotrophin releasing hormone (GnRH) agonists and incomplete luteolysis in GnRH antagonist regimens can result in significant elevations of progesterone. In the late follicular phase, progesterone elevations in GnRH analogue cycles are the result of the ovarian stimulation itself, driven by high follicle stimulating hormone dosage, estradiol levels, the number of follicles and oocytes. It seems that progesterone elevations (> or = 1.5 ng/mL or 4.77 nmol/L) have a detrimental effect on the outcome of pregnancy, accelerating the endometrial maturation. The most appropriate choice to avoid the negative effects of follicular progesterone elevations is to cancel fresh embryo transfer and to transfer frozen–thawed embryos in natural cycles. To prevent follicular phase elevations it might be preferable to use milder stimulation protocols, earlier trigger of ovulation in high responders and single-blastocyst transfer on day 5. The optimal GnRH analogue protocols during the entire stimulation period appear to be the long agonist as well as “long” and long GnRH antagonist regimens. Chinese abstract 这篇综述的目的是分析促排卵期间卵泡黄体激素的来源和作用，体外受精妊娠结局的机制及预防策略。在早卵泡期，促性腺激素释放激素（gonadotrophin releasing hormone，GnRH）激动剂的扳机效应和GnRH拮抗剂中不完整的黄体溶解效应会导致孕激素的升高。在晚卵泡期，GnRH类似物周期孕激素升高是促排卵本身，高卵泡刺激激素用量，雌二醇水平，卵泡和卵母细胞的数量驱动的结果。 孕激素升高似乎（>或=1.5ng/mL或4.77 nmol / L的）对妊娠结局产生不良影响，加速子宫内膜成熟。避免卵泡黄体激素升高的负面影响， 最合适的选择是取消新鲜胚胎移植，而在自然周期移植解冻的胚胎。为避免卵泡期卵泡黄体激素升高，可以使用温和的刺激方案，对高反应者进行较早的排卵诱发，并在第5天进行单个囊胚移植。在整个刺激周期最佳的GnRH类似物方案似乎是长激动剂“长”和长GnRH拮抗剂方案。

Preovulatory progesterone rise during ovarian stimulation for IVF

Abstract The aim of this review is to analyze the relationship between the preovulatory progesterone (P) rise and the in vitro fertilization (IVF) pregnancy outcome. It also investigates the sources and effects of P level increase, including the underlying mechanisms and potential strategies in preventing its elevation during ovarian stimulation. The origin of production of P in the early follicular phase is adrenal which shifts toward the ovaries prior to the ovulation. Several factors contribute to the etiology of P level increase including the number of multiple follicles, the overdose of gonadotropins and poor ovarian response. Nowadays, the influence of the preovulatory P rise on IVF outcome remains controversial. Several authors have failed to demonstrate any negative impact, while others reported a detrimental effect associated with the rise of P. It seems that P rise (≤1.5 ng/ml or 4.77 nmol/l) may have deleterious effects on endometrial receptivity, namely, accelerating the endometrial maturation process that subsequently narrows the time-frame for implantation and thus decreases pregnancy rates. To prevent a P rise, it might be preferable to use milder stimulation protocols, earlier trigger of ovulation, cryopreservation of all embryos and transfer in the natural cycle.