Julian Jenkins

Assisted conception following poor ovarian response to gonadotrophin stimulation

Despite advances in assisted conception which now provide azoospermic men with a realistic alternative to donor sperm, poor ovarian response to gonadotrophin stimulation remains a problem, which may lead women to consider the use of donor oocytes. This review will describe what is meant by poor response to gonadotrophin stimulation and consider its underlying causes and clinical significance. Finally, the prediction and management of poor response will be critically discussed.

Distinction between early and late ovarian hyperstimulation syndrome

OBJECTIVEnTo compare patient and cycle characteristics among three study groups: early ovarian hyperstimulation syndrome (OHSS), late OHSS, and non-OHSS.nnnDESIGNnProspective observational study.nnnSETTINGnUniversity assisted conception service.nnnPATIENT(S)nWomen undergoing in vitro fertilization, intracytoplasmic sperm injection or gamete intrafallopian transfer treatment at Bristol University In Vitro Fertilization Service between January 1, 1995, and December 31, 1998.nnnINTERVENTIONnNone.nnnMAIN OUTCOME MEASURE(S)nPatient age, prevalence of polycystic ovaries, gonadotropin requirement, peak serum estradiol (E(2)) concentration, number of oocytes retrieved, clinical pregnancy rate, number of gestation sacs, and severity of OHSS.nnnRESULT(S)nWomen with early OHSS had significantly higher serum E(2) levels and lower gonadotropin requirements than did the other groups. Cycles with either early or late OHSS had significantly more oocytes collected than those without OHSS. Serum E(2) and oocyte numbers did not accurately predict the risk of developing late OHSS. Clinical pregnancies occurred in all cycles with late OHSS, and multiple pregnancies were significantly more frequent in the late OHSS group than in the other groups. Late OHSS was more likely than early OHSS to be severe.nnnCONCLUSION(S)nEarly OHSS relates to excessive preovulatory response to stimulation, whereas late OHSS depends on the occurrence of pregnancy, is likelier to be severe, and is only poorly related to preovulatory events.

Increased follicular fluid total and free cortisol levels during the luteinizing hormone surge.

OBJECTIVEnTo determine the changes in follicular fluid (FF) total and free cortisol during the LH surge in naturally ovulating women.nnnPATIENT(S)nTwenty-six women having diagnostic laparoscopy during the follicular phase of normal menstrual cycles were selected.nnnINTERVENTION(S)nBlood samples were collected 1 day before, the day of, and 1 day after surgery and the results of serum E2 and LH were used to divide the cycles retrospectively into pre- and post-LH surge groups. Follicular fluid was collected during laparoscopy.nnnMAIN OUTCOME MEASURE(S)nSerum P, total and free cortisol, and FF volume, E2, P, total cortisol, and free cortisol were measured on the day of surgery.nnnRESULT(S)nMedian serum and FF P levels were significantly higher in the post-LH surge group compared with the pre-LH surge group (0.54 versus 1.54 ng/mL [1.7 versus 4.85 nmol/L] and 5.03 versus 28.0 micrograms/mL [15.8 versus 88.0 mumol/L], respectively). Follicular fluid volume also increased significantly after the surge (2.5 versus 4.5 mL). Median serum total and free and percent free cortisol were higher after the surge, although not significantly. In contrast, FF total, free, and percent free levels increased dramatically between pre- and post-LH surge samples (4.41 versus 43.6 ng/mL [16.0 versus 158 nmol/L], 0.138 versus 6.68 ng/mL [0.5 versus 24.2 nmol/L], and 3.3% versus 15.0%, respectively; P < 0.05).nnnCONCLUSION(S)nAn increase in total and free cortisol occurs in the follicle during the LH surge. Cortisol and its regulation by 11 beta-hydroxysteroid dehydrogenase therefore may exert a physiologic role in oocyte maturation or ovulation.

Review of the evidence base of strategies to prevent ovarian hyperstimulation syndrome

The English-language literature was reviewed to examine the evidence base for strategies that have been used to prevent ovarian hyperstimulation syndrome (OHSS). Prediction of OHSS by pretreatment patient characteristics and ovarian response parameters is unreliable, with a significant number of OHSS cases occurring in patients not thought to be high risk, while the majority of ‘high-risk’ cycles do not result in OHSS. Alternatives to ovarian stimulation should always be considered, depending on the clinical situation. Monofollicular ovulation induction with a cautious step-up regime carries a lower risk of overstimulation than step-down regimes. In in vitro fertilization (IVF) cycles, a low starting dose of follicle-stimulating hormone (FSH) and the use of 5000 iu human chorionic gonadotrophin (hCG) for final follicular maturation may benefit patients at high risk of OHSS. The role of GnRH antagonists is unclear. In women with polycystic ovaries, who are undergoing ovarian stimulation for IVF, metformin co-treatment may reduce the risk of OHSS. Coasting of cycles with over-response is associated with a reduced risk of OHSS, although precise criteria for initiating and ending coasting are not definable at present. Elective cryopreservation of all embryos prevents late OHSS, but its value has been poorly researched. The literature does not support a role for intravenous albumin, administered around the time of oocyte retrieval, in preventing OHSS. Evidence is insufficient regarding a possible role for hexa-ethyl starch. hCG should not be used for luteal support, as it is associated with a higher risk of OHSS, and equivalent pregnancy rates are obtained with the use of progesterone.

The relation between immunoglobulin G antibodies to Chlamydia trachomatis and poor ovarian response to gonadotropin stimulation before in vitro fertilization

OBJECTIVEnTo determine whether a relation exists between previous exposure to Chlamydia trachomatis and impaired ovarian response to gonadotropin stimulation.nnnDESIGNnControlled clinical study.nnnSETTINGnTwo university IVF centers.nnnPATIENT(S)nTwo hundred forty-two patients receiving IVF treatment and 81 control patients. Ninety-four patients with a poor response to IVF, defined by cycle cancellation in response to a daily stimulation dose of 300 IU of FSH, and 148 patients with a good response were matched for age. Twenty-eight pregnant controls and 53 controls of proven fertility also were included.nnnINTERVENTION(S)nSerum samples were obtained from patients and controls. Serum levels of immunoglobulin (Ig) G antibodies to C. trachomatis were determined by ELISA.nnnMAIN OUTCOME MEASURE(S)nThe prevalence of serum IgG antibodies to C. trachomatis in critically defined poor responders was compared with that of age-matched good responders.nnnRESULT(S)nA significantly higher proportion of poor responders had serum IgG antibodies to C. trachomatis compared with good responders (44.7% and 30.4%, respectively). Patients undergoing IVF had a significantly higher prevalence of IgG antibodies to C. trachomatis (36%) than did either pregnant or nonpregnant controls (12%).nnnCONCLUSION(S)nA significantly higher prevalence of serum IgG antibodies to C. trachomatis was observed in critically defined poor responders, suggesting a possible detrimental effect of C. trachomatis on subsequent ovarian function.

Serum vascular endothelial growth factor levels are poorly predictive of subsequent ovarian hyperstimulation syndrome in highly responsive women undergoing assisted conception

OBJECTIVEnTo determine whether serum vascular endothelial growth factor (VEGF) levels can distinguish highly responsive women who subsequently develop ovarian hyperstimulation syndrome (OHSS) from women with a similar ovarian response who do not.nnnDESIGNnProspective controlled study.nnnSETTINGnUniversity IVF unit.nnnPATIENT(S)nWomen undergoing IVF who met predetermined risk criteria for OHSS. Patients developing OHSS were compared with patients who did not develop OHSS.nnnINTERVENTION(S)nLong-protocol pituitary down-regulation followed by FSH stimulation by a standard protocol without coasting. A maximum of three embryos was transferred. Vaginal progesterone was used for luteal support.nnnMAIN OUTCOME MEASUREnOccurrence of OHSS; serum VEGF concentrations on the day of embryo transfer (ET) and at 5 and 10 days after ET.nnnRESULTSnSerum VEGF levels at any time point did not differ significantly between 9 OHSS cases and 9 controls. Vascular endothelial growth factor levels in samples collected from cases before the onset of OHSS were higher than levels in time-matched samples from controls (medians, 177.6 [range, 64.02-549.1] pg/mL vs. 100.7 [range, 37.59-246] pg/mL, respectively), but the difference failed to reach statistical significance (P=.0518), and there was considerable overlap between cases and controls.nnnCONCLUSIONSnSerum VEGF levels in the luteal phase do not distinguish between high-risk women who subsequently develop OHSS and women with a similar risk profile who do not develop OHSS.

Periovulatory human oocytes, cumulus cells, and ovarian leukocytes express type 1 but not type 2 11β-hydroxysteroid dehydrogenase RNA

OBJECTIVEnTo further elucidate cortisol metabolism in the follicular microenvironment at the time of oocyte retrieval, the presence of 11beta-hydroxysteroid dehydrogenase (HSD) messenger (m)RNA transcripts in oocytes; cumulus cells; granulosa cells; and CD45(+), CD15(+) leukocytes was assessed semiquantitatively.nnnDESIGNnControlled study using semiquantitative assessment of 11beta-HSD mRNA.nnnSETTINGnUniversity IVF center.nnnPATIENT(S)nTwenty-six patients undergoing controlled ovarian hyperstimulation for assisted conception.nnnINTERVENTION(S)nMetaphase II oocytes; cumulus cells; granulosa cells, and CD45(+), CD15(+) leukocytes from individual follicular fluid aspirates.nnnMAIN OUTCOME MEASURESnSemiquantitative analysis of PCR products after total RNA extraction and complementary DNA synthesis.nnnRESULT(S)nPeriovulatory human oocytes; cumulus cells; CD45(+), CD15(+) leukocytes; and granulosa cells consistently express type 1 but not type 2 11beta-HSD mRNA. Expression of mRNA is greatest in cumulus cells. Type 1 11beta-HSD mRNA expression varies considerably in all cell types and among individual follicles and patients.nnnCONCLUSION(S)nThese studies of mRNA expression suggest that the enzymes present both in and around the periovulatory oocyte will favor a high-cortisol environment.

The choice of luteal support following pituitary down regulation, controlled ovarian hyperstimulation and in vitro fertilization

Gonadotrophin releasing hormone agonists (GnRH-a) are now widely used for pituitary down regulation during in vitro fertilisation (IVF) cycles, to lower the cancellation rate and increase the number of follicles recruited following controlled ovarian hyperstimulation. Although luteal phase support has been shown to be beneficial during such treatment, it is less clear what form this luteal support should take2. It is important to consider what luteal support may be required and how this could be achieved. The efficacy of the various luteal support regimens may then be evaluated with regard to patient convenience and side effects of treatment. It has been suggested that the correct sequence and concentration of the sex steroid hormones may be crucial to prepare the endometrium for successll implantation and to support early intrauterine development3. Progesterone is crucial for implantation4 as it induces secretory changes in the endometrium essential for implantation to occur. However, serum levels of progesterone do not always correlate with expected histological findings5 and local factors acting at the site of implantation are also likely to be important, not to mention the quality of the embryo3. It is thus difficult to establish the minimum progesterone requirement, which is further complicated by the lack of standardised progesterone assays6. In contrast it has been suggested that oestrogens may not be essential for implantation and early intrauterine developmenp. In the absence of oestrogens, progesterone can induce secretory maturation in the endometrium of the primed rhesus monkey and human uterus, suggesting that progesterone alone may support implantation4. Supraphysiological levels of oestrogens inhibit implantation in mice and may have an adverse effect on implantation during human IVF cycles*. Experience of steroid requirements with oocyte donation cycles led de Ziegler in 199S9 to suggest that the crucial factor for implantation is not the absolute values of progesterone nor oestrogen nor their ratio but the duration of exposure to proges-

Effects of assisted hatching method and age on implantation rates of IVF and ICSI.

The objective of this study was to investigate whether a change in assisted hatching (AH) technique from total to partial penetration of the zona pellucida improved the outcome of IVF and intracytoplasmic sperm injection cycles where AH was indicated. This was an observational study conducted from the beginning of January 2000 to the end of April 2005. Total AH was performed in 312 cycles, while partial AH was performed in 592 cycles. In women of all ages, implantation, clinical pregnancy and live birth rates were higher in the partial AH group than in the total AH group (12.6 versus 7.2%, P = 0.0001; 22.3 versus 15.7%, P = 0.02; 18.2 versus 12.5%, P = 0.03 respectively). The benefit of partial AH was most marked in women under 38 years old (i.e. the recurrent implantation failure group). The authors conclude that partial AH is associated with higher implantation and pregnancy rates than total AH, especially in women under 38 years old who suffer from recurrent implantation failure.

Ovarian hyperstimulation syndrome: an endocrinopathy?

Ovarian hyperstimulation syndrome remains a significant but incompletely understood complication of ovarian stimulation. Evidence has accumulated regarding a role for various cytokines, in particular vascular endothelial growth factor, in its occurrence. However, the pathogenesis of ovarian hyperstimulation syndrome is likely to be complex and may involve a network of interacting cytokines and endocrine factors. Recent studies suggest links between specific cytokines and specific functional abnormalities in severe ovarian hyperstimulation syndrome. Two clinical forms of ovarian hyperstimulation syndrome may be distinguished, based on time of onset, with implications for the prediction and prevention of ovarian hyperstimulation syndrome in clinical practice.