Implanon contraceptive implants: effects on carbohydrate metabolism.

The objective of the study was to assess the possible differences in effects of Implanon and Norplant implants on carbohydrate metabolism. This is a 2-year open randomized study of 80 implant (Implanon and Norplant) acceptors. Oral glucose tolerance test (OGTT) was performed before implant insertion and at 6, 12, and 24 months after implant insertion. Glycosylated hemoglobin A(1)C was measured in fasting samples and plasma samples during OGTT were tested for glucose and insulin levels. There was a significant increase in the area under the curve for both glucose and insulin during OGTT within each group with increasing duration of use. However, there was no significant change in the fasting plasma glucose values. There was no significant difference in the carbohydrate parameters between the two groups during implant use, except for a minimal but statistically significant rise in fasting glycosylated hemoglobin A(1)C levels at 24 months in the Implanon group. Both implants appear to induce mild insulin resistance but no significant change in serum glucose levels. These alterations in carbohydrate metabolism should have no clinical significance in healthy women.

Gynaecology in the new millennium.

Great challenges await the gynaecologist in the 21st century. While advances in medical technology necessitate that gynaecology move more towards a medical discipline than a surgical one, gynaecologists will be expected to play an increasingly important role in the modern woman's life. This fundamental change is influenced by four main factors, namely, the world's aging population, spread of information technology, advances in molecular based medical therapy, and the changing lifestyle of the woman in the next century. Our role cannot get any lesser as we continue to advise, educate and facilitate the lives of women, and we must aspire a new generation of responsible gynaecologists to continue this ambition.

Effect of Implanon use on selected parameters of thyroid and adrenal function.

In this article, the effects of Implanon implant use on thyroid and adrenal function was compared with those of Norplant implants. In this 2-year open randomized study of 80 implant acceptors, we found that both implants may induce minimal changes in thyroid hormones and cortisol levels, possibly secondary to alterations in the respective binding globulins in the serum. These alterations in thyroid and adrenal function would have no clinical significance in healthy women. In the Norplant group, sex hormone-binding globulin levels decreased, whereas increased levels were found in the Implanon users at the end of 2 years. These findings lend support to the fact that etonogestrel, released from Implanon implants, is significantly less androgenic than levonorgestrel, released from the Norplant implants.

The sensitivity of the trivariate analysis using maternal serum alpha-feto protein, human chorionic gonadotrophin and maternal age in screening for fetal aneuploidy in mothers above the age of 35.

This study was undertaken to assess the usefulness of maternal serum human chorionic gonadotrophin, alpha-fetoprotein and maternal age in screening for fetuses with abnormal chromosomes in pregnant women aged 35 years and over. From 1989 to 1991, 1208 women seen at the National University Hospital had karyotyping procedures performed for maternal age > 35 years as well as second trimester serum samples taken for alpha-fetoprotein and human chorionic gonadotrophin. Sixteen (1.3%) chromosomal abnormalities were present. Using cut off risk levels of 1:250 and 1:384, the sensitivity of the analysis in screening for Down's syndrome pregnancies was 71.5% and 86% respectively. For the non Down's chromosomal abnormalities, using cut off risk levels of 1:250 and 1:384, the sensitivity of the analysis was only 22.3% and 33.4% respectively. Thus risk calculations based on the two serum markers and maternal age failed to identify all fetuses with abnormal chromosomes.

5-HT4 receptors in isolated human corpus cavernosum?

The novel serotonin subtype-4 (5-HT4) receptor agonist, SC53116 (SC), produced a limited relaxation of noradrenaline (NA) pre-contracted human corpus cavernosum (CC) smooth muscle in vitro. This effect was not significantly attenuated by the 5-HT4 antagonist SDZ250557 (SDZ). In the presence of (+/-) pindolol (1 microM) and methysergide (1 microM), employed to mask 5-HT1 and beta-adrenergic, and 5-HT2 receptors respectively, SC failed to relax NA pre-contracted CC strips to a greater extent than saline. Functional cAMP dependent relaxation pathways were demonstrated by a significant reduction in NA induced tone by prostaglandin E1 (PGE1) and isopropylnoradrenaline (IPNA), the action of the latter compound was effectively eliminated in the presence of (+/-) pindolol. Relaxation of NA induced tone caused by the nitric oxide donor nitro-glycerine (NTG) was significant and similar in the absence and presence of the 5-HT and beta-adrenergic antagonists. The results of this present study indicate that human corporal smooth muscle does not contain 5-HT4 receptors and that, although compounds like SC act to relax non-vascular smooth muscle via cAMP dependent mechanisms, 5-HT4 receptor agonists may be expected to be of limited utility in triggering cAMP dependent relaxation responses in human CC.

A prospective study on the effects of reformulated 2-rod Norplant implant on haemostasis after five years of use.

OBJECTIVE: To evaluate the long-term effects of the new reformulated 2-rod Norplant implant on haemostasis in a prospective group of subjects who have completed 5 years of use. METHODS: Data from 11 women who have completed 5 years' use of the new reformulated 2-rod subdermal implant from the original 16 women who were recruited and randomized to receive this new improved implant in a comparative study were analysed. Clinical assessment and serial blood sampling were done prior to insertion of implant and after 1, 3, 12, 18, 24, 36, 48 and 60 months of implant use. Each subject served as its own control and Analysis of Variance with Student-Newman-Kuels test was used for statistical analysis. The following parameters were determined: plasminogen activators (t-PA, u-PA), plasminogen activator inhibitor-1 (PAI-1), D-dimer, beta-thromboglobulin (beta-TG), thrombin-antithrombin (TAT)-complex, fibrinogen, Factor VII, platelets, haematocrit and haemoglobin levels. RESULTS: No significant change was observed for t-PA levels in prolonged implant use. u-PA antigen showed a significant decrease whilst D-dimer were significantly elevated at only 24 months of implant use compared to pre-implant level. PAI-1 levels were not significantly changed but fibrinogen and FVII levels increased at 36 months and 42 months of use with enhanced platelet activation shown by beta-TG levels at 24 months. Platelet numbers were not affected by prolonged implant use. Haemoglobin concentration and haematocrit level showed significant fluctuations and then return to pre-implant level by 54 and 60 months. CONCLUSION: Enhanced fibrinolysis with platelet activation at 24 months of implant use were seen during the 60 months of 2-rod reformulated Norplant implant use. Hypercoagulable state was not observed although fibrinogen and FVII levels remain above the pre-implant levels as coagulation activation was not enhanced. The increased haemoglobin and haematocrit levels seen indicate enhanced bone marrow activity. There was no association between the use of reformulated 2-rod Norplant implant over 60 months of use and prothrombotic state.

Effects on hemostasis after two-year use of low dose combined oral contraceptives with gestodene or levonorgestrel.

We studied 67 healthy women who were randomly allocated to receive third generation gestodene (Gynera) or second generation levonorgestrel (Microgynon 30) combination of low-dose estrogen oral contraceptives (OCs) for their hemostatic effects over 2 years. Hemostatic changes were apparent within 3 months of OC use. Hematocrit (Hct) was not affected, but hemoglobin (Hb) concentration decreased by 18 months. Shortened prothrombin time (PT) and activated plasma thromboplastin time (APTT) were associated with elevated fibrinogen within the 12-month use of both OCs. Factor VII was reduced only in Micro 30 during the 18 months of use. Enhanced thrombin-antithrombin (TAT)-complex level was seen at 18 months of Gynera use. Prothrombin fragment1+2 (F1+2) rise was seen at 3 months with Micro 30. Reduced antithrombin III (ATIII) activity was seen at 18 months with Gynera and at 24 months with Micro 30. Increased protein C activity was seen at 3 months and reduced protein S occurred at 18 months of Gynera use. Tissue plasminogen activator (t-PA) activity was enhanced for 6 months in both OCs with raised D-dimer levels for 12 months with Gynera and 6 months with Micro 30. Decreased t-PA antigen was seen at 18 months and decreased urokinaselike plasminogen activator (u-PA) antigen occurred throughout the 24 months of both OCs use. Enhanced u-PA activity was only seen in Gynera users. Elevated plasminogen levels were apparent throughout both OCs use. PAI-1 levels were significantly decreased with Micro 30. With Gynera, the decreased PAI-1 activity was seen only at 18 months and PAI-1 antigen at 12 months. No change in platelets and von Willebrand factor (vWF) were seen in long-term OC use except that beta-thromboglobulin (beta-TG) showed decreased trends reaching statistical significance by 18 and 24 months of Micro 30 use and by 24 months of Gynera use. A further significant decrease in beta-TG, u-PA antigen, ATIII, and protein S levels were seen 3 months after pill stoppage compared with pretreatment levels. Activated protein C resistance (APCR) was negative in all subjects before and during OC use. The study indicated dynamic balance between coagulation and fibrinolysis with no endothelial activation. However, because some hemostatic markers showed wide fluctuations during OC use, a longer term study is warranted to investigate any adverse hemostatic changes that might enhance the risks of venous thromboembolism in Asian subjects known to be less prone to thrombosis.

The classification of gestational trophoblastic disease: a critical review.

Gestational trophoblastic disease defines a group of conditions which arises from the fetal chorion. Two of the most important advances in the management of gestational trophoblastic disease have been the standardisation of terminology, and the concept of risk assignment based on classification or staging systems which allows rationalisation of treatment. Gestational trophoblastic disease is unique as the prognosis is dependent not only on the anatomic extent but also the presence of prognostic factors. A staging system similar to that used for other cancers does not apply to this disease because in most cases diagnosis is bases not on histology but on clinical or biochemical parameters. Metastatic spread to distant organs can occur early, even in the absence of disease in the uterus or pelvis. Staging in gestational trophoblastic disease must include prognostic factors in addition to anatomic extent of disease. Broadly there are two categories of classification in current use. The first is based on the usual staging system as in other cancers, with four stages of disease, but at the same time prognostic factors are incorporated. This has the important advantages of simplicity and uniformity with other staging systems. However the main pitfall is that no recommendations are made for treatment. The other broad category consists of risk tables, based on anatomic spread as well as prognostic factors. Here patients are assigned varying risk scores, with guidelines for multiagent chemotherapy at the outset in high-risk patients to minimise drug resistant disease. The ideal system would be one which has four stages of disease, so that comparison is easier, with recommendations for combination chemotherapy beyond a certain stage of disease.

Expression of 3beta-hydroxysteroid dehydrogenase-5,4-en isomerase activity by infiltrating ductal human breast carcinoma in vitro.

In order to determine whether human mammary tumors could contribute to progesterone synthesis from pregnenolone in breast cancer patients, homogenates of infiltrating ductal primary breast tumors at different stages of malignancy (Stages II and III) obtained from pre- and post-menopausal patients (n = 7, age 37-66 years) were incubated with [7n-3H]pregnenolone as substrate. Controls were heated homogenates instead of fresh homogenates. With the use of reverse-isotope dilution analysis, [3H]progesterone was isolated and characterized. No such metabolite was evident in the control incubations of heat-denatured enzymes. The extent of enzymic conversion varied from 0.02 to 4.0%. The results reveal that activity of 3beta-hydroxysteroid dehydrogenase-5,4-en isomerase that metabolizes pregnenolone to progesterone can be identified with the viable homogenates. It is suggested that there exists a potential for substantial progesterone synthesis in vivo. This conversion may be of considerable clinical, therapeutic, and pathophysiological significance in the patient with breast cancer. The biological impact of this conversion should be a high priority research objective.

Molecular variants of luteinizing hormone in three populations of Southeast Asia.

Three populations of Southeast Asia comprising 191 Chinese, 121 Malays and 150 Indians, were studied with respect to two recently described mutant luteinizing hormone (LH) variants using molecular techniques. One of these variants had Trp8 to Arg8 and Ile15 to Thr15 replacements in exon 2 of the LH beta-subunit, while the other variant possessed Ser102 substitution for Gly102 in exon 3. The exon 2 mutants were in complete linkage disequilibrium. The exon 2 variant had an allele frequency of 0.045 in Chinese, 0.062 in Malays and 0.030 in Indians. The allele frequency of the exon 3 variant was 0.018 in Chinese and null in Malays and Indians. The two LH variants may be markers of interest in studies of disturbed pituitary-gonadal function, menstrual disorders and female infertility.

Arterial embolization for bleeding following hysterectomy for intractable postpartum hemorrhage.

Angiographic embolization is a well documented technique that has been utilized for controlling pelvic hemorrhage. A case is described of a 41-year-old para 3 woman with intractable bleeding following a cesarean hysterectomy for postpartum hemorrhage due to uterine atony and coagulopathy. On angiogram, no bleeding was seen from the uterine vessels. An injection of dye above the origin of the gonadal vessels showed persistent hemorrhage from the left ovarian artery. This report illustrates the importance of intensive resuscitation and supportive measures, and the value of angiographic embolization after failed surgery. It also emphasizes the need to locate the exact bleeding vessel on angiography for embolization to be successful.

Necrotising fasciitis originating from a vulval abscess--a case report.

This article reports a rare case of necrotising fasciitis starting out as a vulval abscess with rapid progression to a potentially lethal condition. Elderly people with medical conditions such as diabetes are especially prone to it. A high index of suspicion and an early surgical consult are essential in improving outcome in this condition. Once diagnosed, aggressive surgical debridement with antibiotic cover is crucial. This is followed up with meticulous nursing care of the large wound till it heals. The various diagnostic points and treatment modalities are also discussed.

Preeclampsia: haemostatic status and the short-term effects of methyldopa and isradipine therapy.

OBJECTIVE: To determine the haemostatic status in preeclampsia and to investigate the effects of short-term use of anti-hypertensive drugs, methyldopa and isradipine. METHODS: Thirty preeclamptic (PE) women admitted to the hospital for observation and treatment were randomized to receive either methyldopa or isradipine for 2 weeks. Their blood pressure were monitored for 24 h before treatment and again at 7 days and 14 days after treatment using the programmable automated ambulatory blood pressure (ABP) monitoring system. Blood sampling was performed before commencement of anti-hypertensive treatment, 7 days and 14 days after treatment and the haemostatic parameters studied was compared before treatment with normal pregnancy and the effect of anti-hypertensive treatment. Nineteen normal pregnant subjects with a total of 30 blood sampling at various gestation and good pregnancy outcome served as controls. The following haemostatic parameters were determined; thrombelastography, fibrinogen, antithrombin III (ATIII), thrombin-antithrombin (TAT)-complex, beta-thromboglobulin (beta-TG), plasminogen activators (t-PA, u-PA), plasminogen activator inhibitors (PAI-1, PAI-2), and plasminogen. RESULTS: Significant lowering of blood pressure was evident at Days 7 and 14 of therapy with either methyldopa or isradipine. Increased mean plasma fibrinogen and decreased ATIII levels were seen in preeclampsia together with decreased u-PA and t-PA activity levels in contrast to increased t-PA antigen and beta-TG. No significant differences were seen for TAT-complex, PAI-1, plasminogen and D-dimer levels although their mean levels were higher than observed in non-pregnant subject except for PAI-2, the level was significantly reduced when compared with normal pregnancy. Two-way analysis of variance showed no significant alteration on all haemostatic parameters studied in preeclamptic women receiving either methyldopa or isradipine after 7 and 14 days of therapy. CONCLUSION: Enhance activation of coagulation was observed together with raised fibrinolysis in normal pregnancy and PE. However, in PE a further reduction in ATIII, u-PA and PAI-2 with increased fibrinogen and platelet activation could lead to an imbalance in the coagulation/fibrinolysis equilibrium which favours fibrin deposition. All these changes seen in PE including the coagulation kinetics were not altered by the short term effects of methyldopa and isradipine even though significantly lowered blood pressure were observed during therapy.

Hormone replacement therapy in the developing countries.

The sales data of oestrogen replacement products for 8 developing countries from 1993 to 1995 were analyzed. The data from Malaysia, Pakistan, Taiwan, Thailand, Indonesia, Philippines and South Korea showed the increasing use of oestrogen replacement products. The total usage however varied widely, from only US$11,153 (Philippines in 1993) to as much as US$6,306,717 (Taiwan in 1995). In Singapore, where oestrogen replacement is an accepted and established form of therapy for the postmenopausal woman, there has been an increase in the usage of the nonoestrogen replacement products. There are multiple reasons for the increasing sales of hormone replacement products in the developing countries and these are explored in this article. In some of the developing countries, for example China and India, hormone replacement therapy has just been introduced. However, in those developing countries in which hormone replacement therapy is already available, sales figures show increasing usage. The future augurs well for hormone replacement therapy.

Partial androgen insensitivity and correlations with the predicted three dimensional structure of the androgen receptor ligand-binding domain.

Genetic defects of the human androgen receptor (AR) can cause a wide spectrum of androgen insensitivity syndromes (AIS) ranging from phenotypic females in those with complete AIS; ambiguous genitalia in partial AIS; to male infertility in minimal AIS. The majority of these defects are due to point mutations resulting in amino acid substitutions. It is however unclear why certain mutations result in partial AIS, whereas others in the same exon cause the complete syndrome. We present a case of partial AIS due to a point mutation affecting codon 758 of the AR ligand-binding domain (LBD) that changed the sense of the codon from asparagine to threonine (N758T). The mutant receptor displayed normal binding affinity to DHT but abnormal dissociation kinetics in both patient's fibroblasts and transfected COS-7 cells. The mutant AR was thermolabile, and resulted in approximately 50% reduction in receptor transactivation capacity when examined with a reporter gene incorporating an androgen-response-element. Although the 3-D structure of AR LBD is not known, the homologous region in a member of the steroid receptor superfamily, retinoid-X receptor (RXR-alpha), has been crystallized, allowing comparison of aligned amino-acid sequences of RXR-alpha and AR. The mutation, N758T, lies in a predicted linker region between the fifth alpha-helix (H5) and the first beta-strand (S1). Generally, mutations leading to partial AIS tend to cluster in the predicted linker regions located between the structural helices of the AR LBD. Most strikingly, the predicted linker regions contain over 70% of the mutant ARs associated with prostate cancer in the LBD. The occurrence of mutations associated with both partial AIS and prostate cancer in the same predicted linker regions, suggest that this clustering is not coincidental and that the predicted linker regions are likely to have important, but subtle, roles in defining androgen binding and ligand specificity.

A delta 4-3-keto pathway for testosterone synthesis in the human spermatozoa.

The ability of human spermatozoa to metabolize pregnenolone to progesterone and progesterone to testosterone was assessed. Sonicated specimens of freshly ejaculated sperm from two groups of husbands (n = 6, age 32-38 years; n = 6, age 30-51 years) of infertile couples in the range of sperm concentration between 237.5 and 568.5, 100.1 and 248.8 millions per ejaculate, were separately incubated with [7n-3H]pregnenolone and [1,2,6,7,16,17-3H]progesterone. Using the classical reverse-isotope dilution technique the desired products [3H]progesterone and [3H]testosterone formed from the respective substrates were isolated and characterized, yielding 1.4 to 12.2% and 3.1 x 10(-2) to 2.0 x 10(-1)%. Such metabolites were not evident in the controls. The results indicate that the human spermatozoa contain the enzymes necessary for the transformation of pregnenolone to testosterone via the delta 4-3-keto route.

A new molecular variant of luteinizing hormone associated with female infertility.

OBJECTIVE: To investigate whether the newly described G1502 to A1502 mutation in exon 3 of the LH beta-subunit gene, causing the amino acid substitution of Ser102 for Gly102, is related to female infertility. DESIGN: Screening of fertile and infertile women for the G1502 to A1502 mutation in the LH beta-subunit gene. SETTING: Clinics and laboratories of the National University Hospital obstetrics and gynecology department, Singapore. PATIENT(S): Two hundred twelve healthy fertile women; 40 infertile women with menstrual disorders, polycystic ovary syndrome, and endometriosis; and 12 women with idiopathic infertility. INTERVENTION(S): Exon 3 of the LH beta-subunit gene was analyzed using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), and PCR-mediated direct DNA sequencing. MAIN OUTCOME MEASURE(S): The PCR products of patients were analyzed by RFLP, and the results were compared with those of fertile controls. DNA sequencing radiographs were compared between two mutation-bearing patients and four controls. RESULT(S): The mutation was identified in only two infertile women with endometriosis; other women studied were found to be negative for this mutation. CONCLUSION(S): The missense mutation in the LH beta-subunit gene may be implicated in female infertility, possibly endometriosis-associated infertility in some women.

The influence of abortion legislation on maternal mortality.

Worldwide some 20 million unsafe abortions take place each year and account for approximately 13% of all maternal mortality and serious complications associated with it, such as sepsis, hemorrhage and trauma. Only a quarter of all women in the world do not have any access to legal abortion, whereas 40% have a legal right to decide for themselves. This liberalization of abortion legislation has seen a tremendous drop in abortion-related maternal mortality. Death from unsafe abortions are almost unknown in countries where abortion is available on request. Reduction of the need for induced abortion through the provision of good family planning services should be an integral part of healthcare. Consistent use of contraception greatly reduces the need for abortion, but it cannot completely eliminate this need. Thus, it is essential that safe medical abortion services should be made available to all women in the world in cases of contraceptive failure.