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Background: Recombinant DNA technologies have been used to develop longer-acting therapeutic proteins. One approach is to introduce sequences containing additional glycosylation sites. Using this technique, a new chimeric gene has been developed containing the coding sequences of the FSH beta-subunit and the C-terminal peptide of the hCG beta-subunit, which bears four O-linked oligosaccharide binding sites. Co-expression of the alpha-subunit and the chimeric FSH beta-subunit produces a new recombinant molecule, named corifollitropin alfa, with a prolonged elimination half-life and enhanced in vivo bioactivity compared with wild-type FSH. Methods: Medline searches by subject and additional searching by hand. Results: Initial studies in pituitary suppressed female volunteers confirmed the extended half-life of the compound. Phase II studies have shown that corifollitropin alfa is able to induce and sustain multi-follicular growth for an entire week in women undergoing ovarian stimulation using GnRH antagonist co-treatment for IVF. Corifollitropin alfa regimens have been developed with dosages of 100 and 150 microg, for patients with body weight 60 kg, respectively. Conclusions: Corifollitropin alfa is the first long-acting hybrid molecule with sustained follicle-stimulating activity developed for the induction of multi-follicular growth along with GnRH antagonist co-treatment for IVF. This new treatment option may be simpler and more convenient for patients compared with conventional long protocols of daily FSH injections in combination with GnRH agonist co-treatment. The safety and efficacy of such regimens is currently being evaluated in large comparative phase III clinical trials. The development of corifollitropin alfa is the first step towards a new generation of recombinant gonadotrophins. [ABSTRACT FROM AUTHOR]

Background: The acceptability and continuation rate of oral contraceptive steroids are limited by unpredictable bleeding and the fear of long-term risks such as breast cancer. By inhibiting ovulation and by altering the receptivity of the endometrium, antagonists of progesterone, such as mifepristone, could be developed as estrogen-free novel contraceptives. Methods: Multicentre, double-blind, randomized controlled trial comparing frequency of amenorrhoea (primary outcome), bleeding patterns, side effects and efficacy in women taking daily 5 mg mifepristone (n = 73) or 0.03 mg levonorgestrel (progestogen-only pill; POP, n = 23) for 24 weeks. Results: More women were amenorrhoeic while taking mifepristone than POP (49 versus 0% P < 0.001), and fewer women bled or spotted for >5 days per month (4 versus 39% P < 0.001). Forty-eight percent of women who took mifepristone for 6 months had cystic glandular dilatation of the endometrium but none showed hyperplasia or atypia. There were no pregnancies in 356 months of exposure in women who used only mifepristone for contraception. Two pregnancies occurred in women taking mifepristone who were also using condoms for dual protection. Conclusions: Daily mifepristone (5 mg) is an effective oral contraceptive pill which has a better pattern of menstrual bleeding than an existing POP (levonorgestrel). [ABSTRACT FROM AUTHOR]

Investigates the in vivo effects of leptin on ovarian steroidogenenis in sheep. Examination of the effect of passive immununization against leptin and direct ovarian infusion of leptin during the early follicular phase; Effect of direct ovarian arterial infusion of the low dose leptin on ovarian oestradiol secretion; Impact of any dose of leptin on gonadotropin concentrations of ovulation.

The Booroola (FecB) phenotype is associated with a mutation in the bone morphogenetic protein (BMP) receptor 1B. The BMP action is important during development; surprisingly the only differences so far observed in adult animals are restricted to the ovaries where precocious development of the antral follicles and increased ovulation rate of mutant ewes is observed. The internal organs of 17 ewes homozygous for the mutation (BB) and 18 wild-type ewes (++) were macroscopically examined and weighed. No macroscopic differences were found, and the weight of the heart, liver, lungs, kidneys, and spleen were similar for both genotypes (P > 0.05). In contrast, the adrenals of BB ewes were lighter than those of ++ ewes (P < 0.05). The effect of the mutation on the adrenal function of cortisol secretion was measured at basal level and after an adrenocorticotrophic hormone challenge, before and after dexamethasone suppression. The Booroola mutation had no effect (P > 0.05) in any of these conditions. These findings indicate that the Booroola mutation also affects the size of the adrenal glands and suggest that the mutated gene could be important in the development of other organs in addition to the ovary. However, in the mutant ewes the function of the adrenal glands is not compromised or it is compensated. [ABSTRACT FROM AUTHOR]

Background: Gemeprost and misoprostol are two of the most widely used prostaglandins in combination with mifepristone for medical abortion in early pregnancy. However, the efficacy and side-effects of those two drugs given vaginally have not been assessed in a randomized trial.Methods: Randomized double-blind controlled trial involving 999 women undergoing an abortion at gestational age < or =63 days who received either 0.5 mg gemeprost (group I, n = 499) or 800 microg misoprostol (group II, n = 500) vaginally approximately 48 h after taking 200 mg mifepristone by mouth. The rate of complete abortion and the side-effects were compared between the groups.Results: A total of 89 cases was excluded from full analysis of outcome because either they aborted after mifepristone alone (n = 2), had an ectopic pregnancy (n = 1), or because the outcome was uncertain as they failed to attend their follow-up appointment (n = 86). The rate of complete abortion was very high (>95%) in both groups but significantly higher after treatment with misoprostol than with gemeprost [436/453 (98.7%) versus 451/457 (96.2%), P = 0.019, difference 2.5%, confidence interval 0.4-4.7%] and there were fewer ongoing pregnancies (n = 1 versus n = 8, P < 0.018). Surgical intervention rose significantly with gestation in women who received gemeprost (P < 0.03) but not with misoprostol. The incidence of side-effects such as diarrhoea (13.7 versus 16.4%) and vomiting (27.8 versus 29.7%) was similar in women who received misoprostol or gemeprost respectively, as was the duration and amount of bleeding.Conclusions: (i) Both regimens using a reduced dose of mifepristone are highly effective methods of inducing abortion in early pregnancy; (ii) vaginal misoprostol is the preferred prostaglandin because it is it is associated with fewer failures than low-dose gemeprost, particularly at gestation > or =49 days. [ABSTRACT FROM AUTHOR]

Many women find the idea of a once-a-month contraceptive pill an attractive concept. Mifepristone has been shown to be effective as a contraceptive if administered in the early luteal phase. We tested the contraceptive efficacy of 200 mg of mifepristone on day luteinizing hormone (LH) + 2 in a group of 32 women who used a fertility monitor to identify the LH surge. We also recruited a control group, comprising 20 women who were trying to conceive. In this group, 12 women conceived during a total of 50 control cycles (probability of pregnancy 0.25–0.32). Women in the treatment group contributed to a total of 178 cycles and there were two pregnancies (probability of pregnancy 0.01). An LH surge was not detected in 34 cycles (19.1%). In 20 cycles (11.2%) this was due to imperfect use while 14 were monitor method failures (7.9%). Treatment with mifepristone in the early luteal phase did not disrupt the cycle length but women reported slight vaginal bleeding in 15% of the cycles. The combination of a home-use fertility monitor with once-a-month administration of mifepristone (especially if mifepristone is administered at the early luteal phase) is an acceptable contraceptive option with minimal side effects. Unfortunately, it is difficult to envisage how an easier way of defining the correct timing, which required less compliance, could be devised. [ABSTRACT FROM PUBLISHER]

Prototype hormonal male contraceptive regimens generally achieve only incomplete suppression to azoospermia with potentially adverse metabolic effects. We have carried out a short-term dose-finding study to investigate the potential of an oral gestogen, desogestrel, with testosterone pellets. Normal men received a single dose of 300 mg testosterone with 75 microg, 150 microg or 300 microg desogestrel daily for 8 weeks (n = 10 per group). LH and FSH were rapidly suppressed, with little difference between groups. Testosterone concentrations fell slightly during treatment with evidence of a linear dosage effect. Plasma inhibin B showed minor changes, but in seminal plasma it was suppressed, becoming undetectable in all men in the 300 microg desogestrel group. There were no significant changes in lipoproteins, fibrinogen or sexual behaviour during treatment, and minor falls in haematocrit and haemoglobin concentration. Sperm concentration fell in a dose-dependent manner, with three men, one man and seven men in the three groups respectively achieving severe oligozoospermia (<3 x 10(6)/ml), and three men achieving azoospermia in the 300 microg group despite the short duration of the study. The combination of oral desogestrel with depot testosterone thus results in profound suppression of gonadotrophin secretion without adverse metabolic or behavioural effects. Desogestrel with a long-acting testosterone preparation is a promising approach to hormonal male contraception. [ABSTRACT FROM AUTHOR]

The prospect of a hormonal male contraceptive is no longer distant. Data on the potential impact of this improvement in contraceptive provision, however, is limited, particularly between different cultures. We have therefore carried out a multi-centre study to assess men's attitudes to proposed novel hormonal methods. Questionnaire-based structured interviews were administered to men in Edinburgh, Cape Town, Shanghai and Hong Kong. Approximately 450 men were interviewed in Edinburgh, Shanghai and Hong Kong, and a slightly larger group (n = 493) in Cape Town to give samples (n > 150) of black, coloured and white men. Knowledge of existing male and female methods of contraception was high in all centres and groups. The majority of men welcomed a new hormonal method of contraception, 44-83% stating that they would use a male contraceptive pill. Overall, a pill was more acceptable than an injectable form (most popularly given at 3-6 month intervals); long-acting implants were least so except in Shanghai. Familiarity with comparable female methods appeared to influence acceptability, for both oral and injectable methods. Hong Kong was the only centre where a male method (condom) was currently the most commonly used; men there appeared to rate the convenience of condoms highly while being least likely to think that they provided effective protection against pregnancy compared to other centres, and were least enthusiastic about novel male methods. The acceptability of potential male hormonal methods of contraception was high in some groups but showed wide variability, determining factors including cultural background and current contraceptive usage. These results suggest that the emerging emphasis that men should have greater involvement in family planning will be substantiated when appropriate contraceptive methods become available. [ABSTRACT FROM AUTHOR]

Totals of 450 women attending family planning clinics in Hong Kong, Shanghai and Edinburgh, and 468 in Cape Town, completed a questionnaire designed to seek their views on a contraceptive pill which would be taken only once each month. At least two-thirds of the women in all centres liked the idea of a once-a-month pill. In Hong Kong, Cape Town and Edinburgh, women preferred a pill which inhibited ovulation to one which inhibited implantation, while in all centres a pill which worked after implantation (early menstrual inducer) was considered unacceptable by over half the women. A pill which was taken after a missed menstrual period was considered preferable in all centres, perhaps because it would not be used every month but rather only if pregnancy had occurred. No demographic characteristics, contraceptive experiences or beliefs were consistently correlated with attitudes towards a once-a-month pill, except that women who would not consider having an abortion were more likely to dislike a method that either prevented, or worked after, implantation. A once-a-month pill is now technically possible, although the major drawback is the need to determine when it should be taken. It is reassuring that many women from a variety of different cultures and with widely different experiences, would find this an attractive approach to contraception. [ABSTRACT FROM AUTHOR]

Therapeutic regimens for the treatment of malignant disease may compromise future fertility. One approach to circumvent this is the cryopreservation of embryos created before treatment for the malignancy. Conventional regimens using gonadotrophin-releasing hormone (GnRH) agonists are time consuming, requiring pituitary down-regulation before gonadotrophin administration, thus the duration of treatment is approximately 20-30 days. GnRH antagonists, however, do not cause an initial stimulation of gonadotrophin secretion and can thus be administered during the later stages of follicular maturation to prevent premature luteinization and ovulation. The duration of ovulation induction/in-vitro fertilization (IVF) treatment is thus reduced. In this study, case histories are reported of six women with newly diagnosed malignancies who requested ovulation induction/IVF prior to chemotherapy or surgery in which we have used the GnRH antagonist Cetrorelix. Gonadotrophin administration was started in the early follicular phase, and Cetrorelix (0.25 mg s.c. daily) was added from day 6 of treatment. Subsequent to human chorionic gonadotrophin (HCG) administration oocytes were recovered and successful fertilization and embryo cryopreservation was achieved in all cases. The median duration of treatment was 12 days (range 8-13, including induction of luteolysis in two patients). These results illustrate the potential use and advantages of a GnRH antagonist in ovulation induction/IVF when the need for immediate initiation of treatment and its duration are critical factors. [ABSTRACT FROM AUTHOR]

Localization of the mRNA α and βa subunits of inhibin has previously been reported in the human gonads during the second trimester. Adrenal inhibin has also been reported in the second trimester for the α βa and βb subunits. Investigations showing localization by in-situ hybridization during the first trimester have not been reported. The results have shown hybridization of the α and βa subunits, throughout the period of development studied, in a variety of tissues including the dorsal and thoracic aortas and pericardium stages 13-22 (βa subunit); liver stages 19-21 (βa) and stages 21-22 (α); mesonephros stages 21 and 22 (βa); gonad stages (α and βa); adrenal stages 19-22 (α); surface ectoderm stages 16-22 (βa); mesenchyme stages 16-22 (βa); amnion stages 13-16 (βa); yolk sac stage 12 (α and βa); cartilage stages 19-22 (βa); and nasal proliferation stages 21 and 22 (βa). When compared with distribution of the protein subunits it was noted that more immunostaining activity was found, suggesting that probes were not sufficiently sensitive enough to detect all levels of mRNA expressed. It can be surmised, therefore, that the lack of visual hybridization of the mRNA cannot preclude the possibility that it is not being translated within the tissue even though hybridization was not apparent. [ABSTRACT FROM PUBLISHER]

Transforming growth factor (TGF) is known to have the ability to modify mitogenic responses of tissues to other peptide growth factors and therefore may contribute to the rapid growth rate of an embryo. Throughout the TGF superfamily there is a similar fundamental molecular architecture. Included in this superfamily are inhibin A, activin A and activin B. It has been shown that activin is a powerful mesodermal inducing factor in the early embryo. The human embryo has shown localization of inhibin in the gonads after 16 weeks gestation but it has not been previously identified in earlier embryos. The inhibin-activin protein was found in a range of tissues including the liver stages 19-21 (α) and stages 19-22 (β); oesophagus stages 19-22 (α and β); stomach stages 21 and 22 (α and β); gut stages 16-22 (α) and 21 and 22 (β); pericardium stages 12-22 (α and β); gonad stages 21 and 22 (β) stage 22 (α); adrenal stages 19-22 (α and β); urogenital system states 21 and 22 (α and β); yolk sac stage 12 (α and β); mesenchyme stages 16-22 (α); surface ectoderm stages 13-22 (α) and stages 16-22 (βa); notochord stages 13-22 (β) and stages 21 and 22 (α); nasal, trachea and bronchi stages 19-22 (α and β) leading to speculation of the role of both subunits. [ABSTRACT FROM PUBLISHER]

The developmental age of an embryo in the first trimester of pregnancy is generally determined by ultrasound scanning and/or by calculation from menstrual age. In the original studies, validation of the estimate of gestational age by ultrasound was not possible as the exact date of conception was unknown. Variation in growth rates of identically aged fetuses has previously been reported after assisted conception and with the use of ultrasound scanning. As these pregnancies were ongoing the accuracy of the scanning results could not be determined. Comparison of scanning and direct measurements after termination of pregnancy and menstrual age were carried out to determine the accuracy in fetal dating. The results suggest that the use of ultrasound scanning to determine gestational age is of less use than previously thought, and that the use of menstrual age is severely limited. [ABSTRACT FROM AUTHOR]