High risk pregnancies in hypopituitary women

BACKGROUND: Various short papers have suggested that pregnancies in women with hypopituitarism are high risk but no formal assessment of pregnancy outcome has yet been reported. METHODS: An audit was carried out concerning the outcome of 18 pregnancies in nine women who underwent ovulation induction in a single centre over 20 years. RESULTS: The live birth rate was 61%, miscarriage rate 28% and mid-trimester uterine death rate 11% with no survivors from four sets of twins. The Caesarian section rate was 100% and half of the live births were on or below the 10th centile for weight. One woman successfully breast-fed. CONCLUSIONS: Women with hypopituitarism have high-risk pregnancies, perhaps because of a uterine defect secondary to endocrine deficiency. Fertility treatment must strive for singleton pregnancies with application of particularly strict criteria to avoid twin pregnancies. Early elective Caesarian section is probably warranted in this group.     

Induction of ovulation after gnRH antagonists

The gonadotrophin-releasing hormone (GnRH) antagonist binds competitively to the receptors and thereby prevents endogenous GnRH from exerting its stimulatory effect on the pituitary cells. This causes suppression of gonadotrophin secretion which occurs immediately after administration of the antagonist. When using GnRH antagonist in controlled ovarian stimulation, ovulation or maturation of the oocyte can, therefore, be induced by a variety of drugs, e.g. native GnRH, recombinant LH or short-acting GnRH agonists. Short-acting GnRH agonists were recommended for triggering ovulation in cases with a high risk of developing ovarian hyperstimulation syndrome (OHSS). Since it is evident that GnRH is required to initiate the LH surge and the oestradiol rise, a single administration of GnRH antagonist during the late follicular phase delays the LH surge. Studies showed that a single s.c. administration of 3 or 5 mg of Cetrorelix in the late follicular stage was sufficient to prevent the LH surge for 617 days. This phenomenon can be used in high responder patients who are prone to OHSS. The question whether this delay has any effect on oocyte quality and maturation still remains unanswered. Overall, there are four uses for GnRH antagonist: (i) using short-acting GnRH agonists for triggering ovulation in cases in which the GnRH antagonist is part of the protocol for ovarian stimulation. Recombinant LH and native LHRH could also be used as triggers of LH surge; (ii) delaying the LH surge in cases prone to OHSS by treatment with GnRH antagonist; (iii) to administer GnRH antagonist during the luteal phase to decrease the activity of corpora lutea; (iv) in polycystic ovarian disease with elevated LH the LH/FSH ratio can be corrected with the injection of GnRH antagonist prior to and during ovarian stimulation.     

Endocrinology: Stimulation of ovarian adenylyl cyclase activity by gonadotrophins during the natural and gonadotrophin-induced cycles in the hamster

In this study we utilized the hamster ovary as a model to investigatethe effects of ovulation induction with gonadotrophin on theactivation of the signal transducer effector system, adenylylcyclase (AC). For this purpose, we prepared membrane particlesfrom the ovary and analysed both gonadotrophin-sensitive ACand non-receptor-mediated activation during a cycle in whichovulation and luteinization were achieved by pregnant mare’sserum gonadotrophin (PMSG)/human chorionic gonadotrophin (HCG)administration. Results were directly compared with AC activationin similarly prepared membranes obtained at different stagesof the natural unstimulated cycle. AC activity was quantifiedby the direct conversion of ATP substrate into cyclic adenosinemonophosphate (cAMP). Measurements of ovarian weights, serumoestradiol and progesterone concentrations provided a solidbase from which to evaluate the functional status of the ovaryat each time period during the natural and stimulated cycles.We found that ovarian membranes contain functional componentsof the AC system and demonstrated that AC is highly dependenton hormonal changes and the functional state of the ovary. Thus,during the natural cycle, ovarian AC showed relatively constantresponsiveness to follicle-stimulating hormone (FSH) throughoutthe cycle, whereas responsiveness to luteinizing hormone (LH)/HCGreached its peak during the luteal phase. On the other hand,during the stimulated cycle, sensitivity to FSH and LH/HCG variedconsiderably, being absent during the peri-ovulatory period.AC responsiveness to gonadotrophins was only regained 48 h afterovulation. Also during the peri-ovulatory period of the gonadotrophin-inducedcycle, stimulation of ovarian AC with non-hormonal activatorsdeclined. However, the rate of cAMP production in response tothese activators remained very high, indicating that despiterefractoriness to gonadotrophins, ovarian AC retained the capacityto generate cAMP at near maximal efficiency. Basal (non-stimulated)activity, guanine nucleotide activation, hormone responsivenessand stimulation by the non-hormonal activators NaF and forskolinwere all significantly increased in comparison with the naturalcycle. Basal activity alone was 7-fold higher than the activityobserved during the unstimulated cycle. These results suggestthat subsequent to exogenous gonadotrophin administration, thetransmembrane effector AC system must be primed for a higherlevel of activity in the ovarian tissue. This priming of theovarian AC system by exogenous gonadotrophin was also evidentwhen the enzyme was measured under conditions allowing maximalactivity, i.e. in the presence of a combination of NaF and forskolin.Maximal AC activity increased 4- to 5-fold compared with thenatural cycle. We conclude that gonadotrophin administrationinducing ovulation causes profound alterations in the expressionof AC in ovarian membranes. Gonadotrophin treatment increasedthe enzyme activity and induced a temporal desensitization toFSH and LH/HCG in the peri-ovulatory period of the stimulatedcycle. Because the gonadotrophin-sensitive AC system representsthe capacity of FSH and LH/HCG receptors to couple and elicita biological response, our results provide new insights intothe cellular mechanisms that regulate ovarian activity duringinduction of ovulation.     

Consensus statement on the bio-safety of urinary-derived gonadotrophins with respect to Creutzfeldt-Jakob disease

Human transmissible spongiform encephalopathies (TSE) encompass a group of rare neurodegenerative diseases. In April 2004, a group of international experts and regulators met in Buenos Aires, Argentina, to review the safety and to reach consensus on the use of urinary-derived gonadotrophins with respect to TSE. Iatrogenic transmission of Creutzfeldt-Jakob Disease (CJD) from pituitary-derived gonadotrophins has been reported, no infectivity in urine has been demonstrated, and no definite cases of transmission via urine have been reported. It is currently not possible to monitor donor urine or finished product for the presence of prions. Therefore the assessment of risk has to be based on the likelihood of infection in urine, the source of the urine, and the capacity of the manufacturing process to remove any adventitious infection. Urine for the production of medicinal products should be obtained from sources that minimize the possible presence of materials derived from subjects suffering from human TSE. As no strong evidence for TSE infectivity in urine exists, it can be concluded that the risk of disease-generating prions and TSE infectivity being present in donor urine is low. Current evidence indicates that, with respect to the risk of TSE infection, urinary-derived gonadotrophins appear to be safe.     

Shb null allele is inherited with a transmission ratio distortion and causes reduced viability in utero.

SHB is an Src homology 2 domain-containing adapter protein that has been found to be involved in numerous cellular responses. We have generated an Shb knockout mouse. No Shb-/- pups or embryos were obtained on the C57Bl6 background, indicating an early defect as a consequence of Shb- gene inactivation on this genetic background. Breeding heterozygotes for Shb gene inactivation (Shb+/-) on a mixed genetic background (FVB/C57Bl6/129Sv) reveals a distorted transmission ratio of the null allele with reduced numbers of Shb+/+ and Shb-/- animals, but increased number of Shb+/- animals. The Shb- allele is associated with various forms of malformations, explaining the relative reduction in the number of Shb-/- offspring. Shb-/- animals that were born were viable, fertile, and showed no obvious defects. However, Shb+/- female mice ovulated preferentially Shb- oocytes explaining the reduced frequency of Shb+/+ mice. Our study suggests a role of SHB during reproduction and development.     

宫腔内人工授精97个周期临床分析

目的 选择84对患者97个周期的宫腔内人工授精(IUI)进行临床疗效分析。方法 按自然周期、克罗米芬(CC) 补佳乐 HCG、克罗米芬(CC) HMG HCG分为三组进行围排卵期IUI技术比较。结果 84对患者进行97含属期IUI，自然周期11个，有1例妊娠，妊娠率0．09％；克罗米芬(CC) 补佳乐 HCG组57个周期，有8例妊娠，妊娠率14．04％：克罗米芬(CC) HMG HCG组29个周期，有6例妊娠，妊娠率20．69％。结论 使用促排卵药物，尤其克罗米芬(CC) HMG HCG组，诱发排卵数目多，子宫内膜厚。妊娠率高。     

Randomized comparison of ovulation induction with and without intrauterine insemination in the treatment of unexplained infertility

The aim of this prospective randomized controlled study wasto determine the possible role of ovulation induction with intrauterineinsemination (IUI) in the treatment of unexplained infertility.A total of 100 patients were randomized to receive ovulationinduction with or without IUI. All patients were treated withlong-course gonadotrophinreleasing hormone analogue (GnRHa),starting in the luteal phase, and exogenous follicle stimulatinghormone (FSH) to induce follicular growth. Ovulation was inducedusing human chorionic gonadotrophin and timed intercourse (TI)was advised 24–48 h later or IUI was effected 36—48h later. Both the cycle fecundities (21.8 and 8.5%) and thecumulative ongoing pregnancy rates after three cycles (42 and20%) were significantly higher (P < 0.03) in the IUI groupthan in the TI group respectively. This is a clear indicationthat ovulation induction with IUI is an effective treatmentmethod for unexplained infertility, but ovulation inductionwith TI has a negligible impact in this large group of patients.     

Complete and partial luteinized unruptured follicle syndrome after ovarian stimulation with clomiphene citrate/human menopausal gonadotrophin/human chorionic gonadotrophin

A total of 31 clomiphene citrate/human menopausal gonadotrophin(HMG)/human chorionic gonadotrophin (HCG)-stimulated cyclesin 28 patients were investigated to determine the fate of eachof the matured follicles. A standard stimulation regimen wasadhered to, and ultrasound as well as hormonal monitoring wasperformed. All follicles were measured by vaginal ultrasoundat –12, +35 and +45 h relative to HCG administration andat 7 days after HCG administration. Of the 220 follicles, 107(48.6%) ruptured. The number of ruptured follicles per cyclewas correlated with the mid-luteal progesterone concentration(r = 0.63, P = 0.0005). The probability of follicular rupturewas related to follicular diameter at 12 h before HCG administration;6% of follicles <12 mm in diameter ruptured compared with87% of follicles 18–19 mm. A complete luteinized unrupturedfollicle (LUF) syndrome was observed in six cycles (20%). Inthese cycles, follicular growth and oestradiol, progesterone,luteinizing hormone (LH) and follicle stimulating hormone (FSH)concentrations at 12 h before HCG administration were similarto those in cycles with follicular rupture. However, mid-lutealprogesterone concentrations were lower in complete LUF cycles(46.97 ± 8.95 nmol/1 versus 108.74 ± 12.27 nmol/1;P = 0.02). These data demonstrate that in stimulated cyclesmany follicles, usually the smaller ones, fail to rupture, evenafter HCG administration. Complete LUF syndrome, despite a strongexogenous ovulatory signal, and the absence of any differencein peri-ovulatory hormonal parameters, indicates that the defectcausing LUF resides in the follicle itself and/or hormonal changesduring the follicular phase.     

Time interval from human chorionic gonadotrophin (HCG) injection to follicular rupture

The aim of this study was to estimate the time interval fromhuman chorionic gonadotrophin (HCG) injection to follicularrupture. Furthermore, it was observed whether there was anyeffect on the pregnancy rate if the insemination was performedat the time of follicular rupture. In a programme of intrauterineinsemination 37 consecutive cycles in 32 patients were monitoredafter stimulation with clomiphene citrate. HCG was administeredby i.m. injection when a leading follicle of at least 18 mmin diameter was observed sonographically. All patients weremonitored by sonography with 1 h intervals from 32 h after HCGinjection until the first rupture of a follicle. Inseminationwas performed immediately after the first follicular rupture.The pregnancy rate was 16% (5/32). In 66%, the largest folliclewas the first to rupture. The mean time interval from HCG administrationto first follicular rupture was 38.3 h (SEM = 0.54; range =34–16). Our findings support the concept that ovulationoccurs about 38 h after HCG administration. The pregnancy ratewas within the normal range, although insemination was performedat the time of follicular rupture. The largest follicle wasnot always the first to rupture     

Induction of ovulation in rabbits by pure urinary Iuteinizing hormone

In 18-week-old nulliparous rabbit dose, ovulation was inducedwith 50 IU of pure urinary luteinizing hormone (LH; LHgroup),or 50 IU of ohuman chorionic gonadotrophin (HCG; HCG group),in order to detemine the effect of these treatments on 17-oestradioland progesterone concentrations, and on oocyte and embryo quality.Luteinizing follicles, recovered oocytes, progesteronoe concentrationand grade 5 embryos were significantly reduced when pure urinaryLH was used. Statistically significant correlations were found:(i) between oestradiol concentration and number of degeneratedoocytes in both groups (positive); (ii) between oestradiol concentrationand grade 1 and 2 embrayos (negative), and grade 5 embryos (positive)in the HCG group; (iii) between progesteronoe concentrationand metaphase II oocytes(negatice), and between progesteroneand grade 5 sembryos (positive), in the HCG group; and (iv)between progesterone and oestradiol concentrations (negative)in the LH group. It seems that the oestrsdiol to progegsteroneratio improves during the early luteal phase when ovulationis induced with LH, and that oestradiol and progesterone concentrationscould play a role in dtermining oocyte and embryo quality