Muhammad Fatum

In vitro maturation or in vitro fertilization for women with polycystic ovaries? A case–control study of 194 treatment cycles

OBJECTIVE To compare the outcome of unstimulated in vitro maturation (IVM) and routine IVF/intracytoplasmic sperm injection (ICSI) for women with polycystic ovaries (PCO). DESIGN Retrospective case-control study. SETTING Fertility unit. PATIENT(S) Ninety-seven patients undergoing IVM were compared with 97 patients undergoing IVF. All had PCO and matched for age, infertility diagnosis, and ovulatory status. INTERVENTION(S) In vitro maturation cycles were unstimulated and hCG was administered 35-40 hours before oocyte retrieval. Oocytes were matured in vitro for 24-48 hours before insemination by ICSI. Endometrial priming with E(2) and P was commenced from the day of egg retrieval and one to two embryos were transferred on days 2-5 of development. Standard long protocol IVF/ICSI was used in the control group. MAIN OUTCOME MEASURE(S) Live birth rate per cycle and ovarian hyperstimulation syndrome (OHSS) rate. RESULT(S) Overall, 65% of IVM eggs matured in vitro in the IVM group. Implantation rates were significantly higher in the IVF group (19.4% vs. 12.9%) as clinical pregnancy rates (50.5% vs. 19.6%) and live birth rates (44.3% vs. 16.5%) than in the IVM group. The OHSS rate was significantly higher in the IVF group (8.2% vs. 0%). CONCLUSION(S) In vitro maturation is a safer and simpler alternative to conventional IVF for women with PCO. It avoids difficulties of gonadotropin stimulation and the risk of OHSS but has a significantly lower live birth rate. Current research projects aim to close the success gap between IVM and IVF.

Deleterious effects of obesity upon the hormonal and molecular mechanisms controlling spermatogenesis and male fertility

Abstract Worldwide obesity rates have nearly doubled since 1980 and currently over 10% of the population is obese. In 2008, over 1.4 billion adults aged 20 years and older had a body mass index or BMI above a healthy weight and of these, over 200 million men and nearly 300 million women were obese. While obesity can have many ramifications upon adult life, one growing area of concern is that of reproductive capacity. Obesity affects male infertility by influencing the hypothalamic–pituitary–gonadal axis, thus causing detrimental effects upon spermatogenesis and subsequent fertility. In particular, evidence indicates that excess adipose tissue can alter the relative ratio of testosterone and oestrogen. Additional effects involve the homeostatic disruption of insulin, sex-hormone-binding-globulin, leptin and inhibin B, leading to diminished testosterone production and impairment to spermatogenesis. Aberrant spermatogenesis arising from obesity is associated with downstream changes in key semen parameters, defective sperm capacitation and binding, and deleterious effects on sperm chromatin structure. More recent investigations into trans-generational epigenetic inheritance further suggest that molecular changes in sperm that arise from obesity-related impaired spermatogenesis, such as modified sperm RNA levels, DNA methylation, protamination and histone acetylation, can impact upon the development of offspring. Here, we summarise our current understanding of how obesity exerts influence over spermatogenesis and subsequent fertility status, and make recommendations for future investigative research.

The case for aromatase inhibitors use in Oncofertility patients. Should aromatase inhibitors be combined with gonadotropin treatment in Breast Cancer patients undergoing ovarian stimulation for fertility preservation prior to chemotherapy? A debate

Abstract Breast cancer is one of the hormone-dependent cancers that may be adversely affected by elevated oestrogen or progesterone concentrations, particularly the endocrine active (hormone receptor positive) breast cancers. Treatment for breast cancer patients aimed at fertility preservation, includes ovarian hyperstimulation, the harvest of oocytes, and subsequent cryopreservation of oocytes or embryos. Classically, gonadotrophins have been used effectively for ovulation induction, a treatment often accompanied by high blood oestrogen concentrations produced by the hyperstimulated granulosa cells. Despite the uncertainty which surrounds this issue and the lack of clear-cut clinical evidence, it is still of major concern that these ensuing high hormone levels might be associated with a high risk of recurrence of the cancer. A growing number of clinical studies have strongly suggested the benefits of using aromatase inhibitors in infertility treatment, both as single agents or as adjuncts to FSH-containing ovulation induction regimes in reproductive medicine. Combining gonadotrophins with aromatase inhibitors would augment the stimulation effect, with a reduced increase in serum concentrations of estradiol. We propose to open a debate over the use of aromatase inhibitors in combination with FSH in ovulation induction treatment of breast cancer oncofertility patients. As the safety of aromatase inhibitors such as letrozole has recently been demonstrated in several studies, and there is growing concern over the possible detrimental effects of high estradiol levels on breast cancer cells (at least in mouse models), the co-administration of letrozole in these patients would reduce both the high supraphysiologic serum levels of estradiol and the intratumoral in situ production of oestrogen. However, since it is unlikely that a well-founded evidence-based justification of this treatment will be formulated in the near future, based on well-designed prospective randomised controlled trials, we advocate a wider use of aromatase inhibitors in combination with gonadotrophins in breast cancer patients, especially those with hormone-receptor-positive tumours.

Grade of the inner cell mass, but not trophectoderm, predicts live birth in fresh blastocyst single transfers.

Abstract Debate continues over which morphological parameter is most important in selecting blastocysts for transfer. We aimed to investigate which parameter more accurately predicts the occurrence of a live birth by designing a retrospective cohort study of 1084 fresh elective single blastocyst transfers. Primary outcome was live birth rate (LBR) and secondary outcomes were implantation, clinical pregnancy and early pregnancy loss rates. Blastocyst expansion and inner cell mass (ICM), but not trophoectoderm, were associated with LBR in the definitive multivariable regression analysis. When ICM grade dropped from A to C the likelihood of achieving a live birth was reduced by 55% (OR= 0.45, 95% CI 0.26-0.79, p = .005). These results were similar for clinical pregnancy rates. Early pregnancy loss rates of embryos with ICM grade C were more than double (38.0%) compared to those of grades A (15.95%) and B (17.17%, p = .002). The transfer of an embryo with an optimal inner cell mass reduces early pregnancy loss and increases the likelihood of a live birth. We did not find any significant association between trophectoderm and LBR in the multivariable analysis in contrast with recent studies.

In vitro maturation and surrogacy in patients with vascular-type Ehlers–Danlos syndrome – A safe assisted reproductive technology approach

Abstract Ehlers–Danlos syndrome (EDS) is an autosomal dominant connective tissue disorder with one of the highest maternal mortality rates of any condition. Patients with the vascular type of EDS are prone to spontaneous arterial and visceral ruptures. The occurrence of these severe and life-threatening complications is increased in pregnancy. Moreover, these patients carry a 50% risk of having an affected child. However, little is known about the risks of assisted conception treatments on these patients. We present the case of a 33-year-old woman suffering from EDS with a history of repeated ruptures of arterial aneurysms and a recently ruptured aneurysm of the splenic artery during her first intracytoplasmic sperm injection (ICSI) cycle who was then advised to undergo only unstimulated cycles. After a few natural ICSI cycles, the patient safely underwent two in vitro maturation cycles with pre-implantation genetic diagnosis in our unit. An unaffected blastocyst was transferred into a surrogate host. To our knowledge, this is the first case of EDS in assisted reproduction technologies including pre-implantation genetic diagnosis to be reported in the medical literature. This case has shown that unstimulated in vitro maturation and pre-implantation genetic diagnosis can safely be offered for vascular-type Ehlers–Danlos patients.

Ovarian Tissue Cryopreservation

In recent years, cryopreservation of ovarian tissue in humans has emerged as a promising technique for fertility preservation in premenarchal children and adolescents, as well as an alternative in adult women prior to starting gonadotoxic chemo/radiotherapy. The prognosis and the survival rates of cancer patients have improved tremendously as a result of recent advances in cancer treatment – particularly in childhood cancers – and therefore attention is now being directed towards quality of life issues and the long-term gonadotoxic side effects of chemotherapy or radiotherapy. The incidence of ovarian failure is dependent on the agents used, the dose, and the age of the patient.

Quintuplets: a rare event following clomiphene citrate therapy.

While the effectiveness of clomiphene citrate in the treatment of oligo-ovulatory women has been demonstrated, its use in unexplained infertility remains controversial. In fact, expectant management, controlled ovarian stimulation plus intrauterine insemination and in vitro fertilization are among the possible treatments options for unexplained infertility. According to the most recent Cochrane review, clomiphene citrate was found to be no more effective than no treatment or placebo for clinical pregnancy or live birth, independent of the use of intrauterine insemination or human chorionic gonadotropin. 2 Clomiphene citrate increases the number of follicles produced per cycle and, therefore, increases the number of potential oocytes to be fertilized. Hence, ovulation induction with clomiphene citrate in unexplained infertility, which by definition includes women with ovulatory cycles, must be done very carefully because it can easily lead to multiple ovulations and multiple pregnancies. Moreover, with no clear positive impact on the live birth rate, clomiphene citrate can definitely be considered as risky, as shown in this Image of the Month. 1 Furthermore, we would like to emphasize the need for close ultrasound monitoring of the follicular response when clomiphene citrate is used in conjunction with gonadotropins. In the case mentioned, human chorionic gonadotropin was used to trigger ovulation, which most probably led to the fertilization of five oocytes. Most high order pregnancies could be averted with ultrasound monitoring which could, if needed, prompt cancellation of the cycle or conversion to rescue IVF. 3