Effect of previous hormone replacement therapy on endometrial polyps during menopause.

The aim of this study was to evaluate the effect of hormone replacement therapy (HRT) on the expression of Ki-67, bcl-2 and c-erb.B2 in endometrial polyps during menopause. Sixteen patients using HRT and 24 untreated controls with endometrial polyps were enrolled in this study. Polypectomy was carried out by hysteroscopy. The presence of c-erb.B2, bcl-2 and Ki-67 expression was determined by immunohistochemistry. HRT was found to decrease Ki-67 and bcl-2 expression in endometrial polyps without affecting the c-erb.B2 staining reaction. HRT may cause endometrial polyp involution by decreasing proliferation and stimulating apoptosis.

Proliferation kinetics in adenomyosis during the menstrual cycle and during oral contraceptive use.

Our objective was to investigate the presence of focal p53 expression in relation to proliferation rates in adenomyotic lesions during the menstrual cycle and in women on oral contraception. Fifty-nine perimenopausal patients with menorrhagia and adenomyosis were submitted to endometrial resection. The procedure was carried out during menstruation (n = 14), during the proliferative phase (n = 15), during the luteal phase (n = 20) or following the use of oral contraceptives (n = 10). The number of Ki-67-positive cells was low during menstruation, during the luteal phase and following the use of progestins. In the proliferative phase, on the other hand, there was a significant increase in the percentage of Ki-67-positive cells. Focal p53 expression was detected mainly during the proliferative phase of the menstrual cycle when proliferation rates were high. PTEN expression was detected in all cases irrespective of the phase of the menstrual cycle or use of oral contraception. We conclude that proliferation rates in adenomyotic lesions undergo marked cyclic variations and this affects the percentage of cases showing focal p53 expression in the glandular epithelium.

Proliferation profile of endometrial polyps in post-menopausal women.

OBJECTIVE: To determine whether or not the presence of c-erbB2 over-expression in endometrial polyps affects the percentage of cells positive for Ki-67 proliferation marker. METHODS: Thirty-five patients with endometrial polyps were submitted to polypectomy by hysteroscopy. Ki-67 and c-erbB2 over-expression were investigated in the polyps by immunohistochemistry. RESULTS: The presence of c-erbB2 over-expression by immunohistochemistry was observed in 80% of endometrial polyps and was associated with higher proliferation rates as determined by the number of positive Ki-67 cell nuclei. In c-erbB2-negative polyps, the proliferation rates were low. CONCLUSION: Ki-67 and c-erbB2 over-expression are frequent in endometrial polyps in post-menopausal women.

Carbohydrate metabolism in sickle cell patients using a subdermal implant containing nomegestrol acetate (Uniplant).

Uniplant, a second-generation contraceptive implant, has been demonstrated to promote a significant improvement in the overall well-being of women with sickle cell anemia. It has been suggested that the discrete increase in blood glucose levels observed in Uniplant users could be a contributory factor for clinical improvement. Ten healthy sickle cell patients were enrolled in the study. An oral glucose tolerance test was performed prior to implant insertion and at 1, 6, and 12 months of therapy. Blood glucose and insulin were measured before and at 30, 60, 120, and 180 min after a 75-g glucose load. The glucose and insulin areas under the curves were calculated. Fasting glycosylated hemoglobin was also measured. No significant changes were observed in glycosylated hemoglobin, glucose or insulin. We conclude that Uniplant is a safe contraceptive for sickle cell patients.

Detection of testosterone and estrogen receptors in the postmenopausal endometrium.

OBJECTIVE: To detect the presence of testosterone and estrogen receptors in the stroma and glandular epithelium in the malignant and non-malignant endometrium. METHODS: One hundred and forty-five consecutively-enrolled peri- or postmenopausal patients were submitted to diagnostic or operative hysteroscopy. These patients either had a history of abnormal uterine bleeding or they were asymptomatic with an endometrial echo greater than 4 mm. The presence of estrogen and testosterone receptors was determined in endometrial samples by immunohistochemistry, using monoclonal antibodies and a streptavidin-biotin peroxidase complex system with diamino benzidine as the chromogen. RESULTS: Testosterone receptors were detected mainly in the stroma in the non-malignant endometrial lesions and in the atypical glandular epithelium in cases of estrogen-positive endometrial carcinomas. CONCLUSIONS: The presence of testosterone receptors in estrogen receptor positive endometrial carcinomas may be involved in the mechanism of cell proliferation in these tumors. The strong staining reaction for testosterone receptors in the endometrial glands can be considered one of the features of invasive malignancy.

Gossypol blood levels and inhibition of spermatogenesis in men taking gossypol as a contraceptive. A multicenter, international, dose-finding study.

The safety and efficacy of gossypol continues to be controversial. The aim of this study was to evaluate gossypol as a contraceptive pill for men at doses lower than those previously prescribed and in men from various ethnic origin. A total of 151 men from Brazil, Nigeria, Kenya, and China were divided into two groups. Both groups received 15 mg gossypol/day for 12 or 16 weeks to reach spermatogenesis suppression. Subjects were then randomized to either 7.5 or 10 mg/day for 40 weeks. In addition, 51 men were enrolled as a control group. In all, 81 subjects attained spermatogenesis suppression. Only one man discontinued treatment because of tiredness. Potassium levels fluctuated within the normal range. FSH increased consistently. Testicular volume decreased, but after discontinuation, values returned to levels not statistically different from admission. Of 19 subjects on the 7.5 mg/day dose group, 12 recovered sperm counts >20 million/mL within 12 months of discontinuing gossypol. In the 10 mg/day group, sperm counts recovered in only 10 of 24 subjects. Eight of the 43 patients remained azoospermic 1 year after stopping gossypol. All men diagnosed with varicocele failed to reverse spermatogenesis suppression. Gossypol blood levels indicated that sperm suppression occurs independently of concentration, whereas spermatogenesis recovery appears to be concentration-dependent. Gossypol may become a medical alternative to surgical vasectomy when the delay in onset of infertility is acceptable. When taken for 1 year, gossypol causes no reduction in sexual desire or frequency of intercourse. The possibility of reversal, occurring in 51% of the men on this regimen within 1 year after stopping gossypol, is an advantage of this compound as compared with surgical sterilization in many parts of the world.

PIP: The safety and efficacy of gossypol continues to be controversial. The aim of this study was to evaluate gossypol as a contraceptive pill for men at doses lower than those previously prescribed and in men from various ethnic origin. A total of 151 men from Brazil, Nigeria, Kenya, and China were divided into two groups. Both groups received 15 mg gossypol/day for 12 or 16 weeks to reach spermatogenesis suppression. Subjects were then randomized to either 7.5 or 10 mg/day for 40 weeks. In addition, 51 men were enrolled as a control group. In all, 81 subjects attained spermatogenesis suppression. Only 1 man discontinued treatment because of tiredness. Potassium levels fluctuated within the normal range. FSH increased consistently. Testicular volume decreased, but after discontinuation, values returned to levels not statistically different from admission. Of 19 subjects in the 7.5 mg/day dose group, 12 recovered sperm counts higher than 20 million/ml within 12 months of discontinuing gossypol. In the 10 mg/day group, sperm counts recovered in only 10 of 24 subjects. 8 of the 43 patients remained azoospermic 1 year after stopping gossypol. All men diagnosed with varicocele failed to reverse spermatogenesis suppression. Gossypol blood levels indicated that sperm suppression occurs independently of concentration, whereas spermatogenesis recovery appears to be concentration-dependent. Gossypol may become a medical alternative to surgical vasectomy when the delay in onset of infertility is acceptable. When taken for 1 year, gossypol causes no reduction in sexual desire or frequency of intercourse. The possibility of reversal, occurring in 51% of the men on this regimen within 1 year after stopping gossypol, is an advantage of this compound as compared with surgical sterilization in many parts of the world.

Use of a single implant of elcometrine (ST-1435), a nonorally active progestin, as a long acting contraceptive for postpartum nursing women.

Because of its unique features, the contraceptive effectiveness and tolerance during breast-feeding of 16-methylene-17 alpha-acetoxy-19-nor-4-pregnene-3,20-dione (elcometrine), delivered within a single subdermal capsule of medical grade polydimethylsiloxane, was investigated. Unlike other progestational steroids, elcometrine has no affinity for androgen and estrogen receptors and is inactive by the oral route. A total of 66 breast-feeding women receiving elcometrine by the subdermal route were enrolled in the study, and 69 women who elected to use Copper-T380 intrauterine devices (IUD) served as control subjects. The women and their infants were observed until the end of the first postpartum year. There were no significant differences in growth and development measurements among the infants in the elcometrine and control groups. The percentage of infants continuing to breast-feed at 3 and 6 months was significantly higher in the elcometrine group. There were no significant differences between the concentration of elcometrine in the mother's blood and milk. At 75 days, blood levels of elcometrine in the infants were near the undetectable and were significantly lower than the levels in maternal blood or milk (p < 0.01). In 15 of 25 infants, blood levels of elcometrine were at the limit of assay sensitivity or undetectable. Two pregnancies occurred in women using IUD, whereas none occurred in those using implants. There were menstrual bleeding irregularities in both groups. A single elcometrine capsule placed subcutaneously at 6-monthly intervals appears to be an effective method of contraception for lactating women and results in blood concentrations of nursing infants at or near undetectable levels.

PIP: Discusses the effects of the use of a single implant of elcometrine (ST-1435), a nonorally active progestin, as a long acting contraceptive for postpartum nursing women in Maternidade Climerio de Oliveira in Salvador, Bahia, Brazil. A total of 135 women aged 18-35 years having a singleton term delivery, fully breast-feeding on demand, planning to breast-feed for 6 months postpartum, and requesting effective contraception were recruited. The method was initiated for 6 weeks postpartum. Results showed that 66 breast-feeding women used elcometrine implants, while 69 women preferred an IUD insertion. The contraceptive efficacy of lactation is high for women breast-feeding on demand, particularly in those who remain in amenorrhea during the 6 months postpartum; in these women, elcometrine implant and IUD prevented pregnancy effectively. Breast-feeding was significantly higher (p 0.05) in the elcometrine group at 3 and 6 months, while at 9 and 12 months there was no statistical difference. The differences in type, frequency of supplementary feeding, and anthropometric measures between the two contraceptive groups were not significant. Menstrual irregularities were present in both groups. Thus, elcometrine could be best alternative and the most effective method of contraception for lactating women.

[Acute complications of diabetes mellitus]. / Complicações Agudas da Diabetes Mellitus.

A retrospective study was made of 83 diabetic patients admitted to the Department of Internal Medicine between January 1986 and December 1993, with acute intercurrence of the disease. The authors considered some clinical features (age, type and frequency of complication, form of presentation, causal aetiology, laboratory findings and therapeutic options). Statistical relationships between different populations were made using the unpaired Student's T. method. Results were compared with those in the literature, leading to some significant conclusions.

Results of a user satisfaction study carried out in women using Uniplant contraceptive implant.

A study of the acceptability of Uniplant, a 12-month single implant of nomegestrol acetate, included 819 women from Africa, Latin America, and China, participating in a clinical trial of Uniplant. A standard, pre-coded questionnaire was specially designed for this purpose and applied at the moment of removal of implant, either at the end of 12 months of use or at the time of discontinuation for whatever reason. The level of satisfaction proved high when users' comparison with their previous contraceptive method, users' recommendation of Uniplant to others, users' intention to use the method in the future, and service satisfaction were taken into consideration. Uniplant was considered easy to use, safe (low risk of pregnancy), and also to cause fewer side effects than other methods. When asked about the least liked feature of Uniplant, almost half the respondents said that there was nothing that they disliked and about one-third mentioned the changes in their menstrual pattern. However, according to the clinical trial, over half of the Uniplant users have bleeding patterns similar to untreated cycles. The majority of respondents did not feel any discomfort during the procedure of insertion and removal of the implant. About 70% of patients in the study stated that they required contraception for more than one year and most of these women said that they did not mind having to change the implant every year.

Multicenter clinical trial on the efficacy and acceptability of a single contraceptive implant of nomegestrol acetate, Uniplant.

Uniplant, a single Silastic implant containing nomegestrol acetate, provides contraceptive efficacy for one year. Uniplant use for one year was studied in 1,803 healthy women of reproductive age, enrolled from 10 centers in 9 countries, after informed consent. Implants were placed subdermally either in the upper arm or in the gluteal region. Two-hundred-seventy-six subjects discontinued prior to completing one year of study. Cumulative discontinuation rate at 12 months was 15.72%. Medical reasons for discontinuation were principally menstrual-related. Fifteen pregnancies occurred during the one year study period, resulting in a 12-month net cumulative pregnancy rate of 0.94%. Approximately 56% of subjects using Uniplant had bleeding patterns similar to normal menstruation. Results from this study confirm that Uniplant is an efficient, well tolerated, 12-month contraceptive implant, with the advantage of easier insertion and removal of the single implant compared to other multiple implant methods.

Androgen levels in women using a single implant of nomegestrol acetate.

This study was undertaken to evaluate the effects of a single implant containing nomegestrol acetate (Uniplant) on plasma levels of sex hormone-binding globulin (SHBG), testosterone, free testosterone, androstenedione and on blood pressure, body weight, and the development of acne vulgaris. Plasma levels of sex hormone-binding globulin, testosterone, free testosterone and androstenedione were measured. Blood pressure and body weight were determined. The development of acne vulgaris was evaluated. Total testosterone and androstenedione decreased significantly during two years of Uniplant use but all levels were within the normal range. There were no significant differences in sex hormone-binding globulin and free testosterone during 24 months of Uniplant use. All changes observed in this study were within normal range. SHBG was not affected by Uniplant use. No significant increase in androgen levels and in the development of acne vulgaris was observed in these women using nomegestrol acetate implant during two years. Based on these results, it is possible to conclude that Uniplant had no androgenic effect in women during this study.

PIP: In Bahia, Brazil, clinical researchers enrolled 18 women of reproductive age into a clinical study examining the effects of a single contraceptive implant (Uniplant) on plasma levels of sex hormone-binding globulin (SHBG), testosterone, free testosterone, androstenedione, and on blood pressure, body weight, and the development of common acne. They followed the women for 24 months. The implant consisted of silastic tubing filled with 55 mg crystalline, finely ground nomegestrol acetate. The implant did not significantly change the plasma level of SHBG (69.2 nmol/l at baseline and 59.8 nmol/l at 24 months). The plasma level of total testosterone fell from 1.9 to 1.2 nmol/l at 12 months (p 0.01) and to 0.8 nmol/l at 24 months (p 0.01) (p = 0.019 for entire study period). Yet all these levels fell within the normal range. The free testosterone plasma level did not change significantly (2.6 pmol/l at baseline and at 24 months). The plasma level of androstenedione fell steadily throughout the study period (8.7 nmol/l at baseline, 6.2 at 6 months, 4.8 at 12 months, 3.3 at 18 months, and 3.2 at 24 months; p = 0.029), probably a result of ovulation inhibition. Body weight increased from 54.7 kg at baseline to 55.3 kg at 12 months (p 0.01) and to 56 kg at 24 months. Between baseline and 12 months of Uniplant use, both systolic and diastolic blood pressure increased (p 0.01) but did not change significantly thereafter. No woman developed acne. These findings indicate that Uniplant does not induce an androgenic effect in women during two years of use.

Effects of an implant of nomegestrol acetate, a 19-nor-progesterone derivative, on thyroid function.

This study was undertaken to assess tri-iodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), T3 uptake, free T3 and free T4 in nomegestrol acetate implant (Uniplant) users. A total of eighteen volunteers of reproductive age who wanted to avoid conception were enrolled in the study. All subjects were investigated before starting treatment. Blood samples for hormonal analysis were taken prior to insertion of the implant. Thereafter, blood samples were drawn at 3, 6, 12, 18 and 24 months of Uniplant use. All subjects had used non-hormonal contraceptives for at least 6 months prior to insertion of the implant. The results observed in this study showed that there was no significant difference in tri-iodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) during two years of Uniplant use. No significant difference was found in free T3 levels during two years of Uniplant use. A significant decrease was observed in T3 uptake (p < 0.05) in month 24 and in free T4 (p < 0.05) in month 3 of Uniplant use. All changes observed in this study were inconsistent and all levels were within the normal range.

The effects of nomegestrol acetate subdermal implant (Uniplant) on carbohydrate metabolism, serum lipoproteins and on hepatic function in women.

This study was undertaken to assess possible variations in body weight, blood pressure, fasting glucose, HbA1C, insulin, total cholesterol, HDL-C, LDL-C, triglycerides, SGPT, SGOT, GGT and bilirubin in women bearing a single subdermal Silastic implant containing 55 mg (10%) of nomegestrol acetate during two years. A total of eighteen volunteers of reproductive age who desired to avoid conception were enrolled in this study. Subjects were healthy women with no contraindications to hormonal contraception. All women were investigated before starting treatment and were followed up for one year. At the end of one year the capsules were removed and a new capsule was inserted. Fasting blood samples were drawn at 8:00 to 8:30 am twice prior to implant insertion and then at the first, third, sixth and twelfth months and every six months thereafter. Body weight increased from 54.9 +/- 1.5 kg at admission to 55.3 +/- 2.0 kg at 12 months of use (p < 0.05) and to 56.0 +/- 2.7 kg at 24 months of use. A slight increase in both systolic and diastolic blood pressure was recorded at month 12 (p < 0.01). At month 24, blood pressure was not significantly different from admission values. All levels were within the normal range. Insulin, HbA1C, LDL-C and GGT remained unchanged during twenty-four months of Uniplant use. A significant decrease in total cholesterol (p < 0.05) was observed in the third month while a significant decrease in HDL-C (p < 0.01) was observed only in the sixth month of Uniplant use.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: Possible variations in body weight, blood pressure, fasting glucose, HbA1C (glycosylated hemoglobin), insulin, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides, serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), GGT, and bilirubin were assessed for 2 years. 18 healthy female volunteers with a mean age of 23.0 years and mean parity of 0.9 used a single subdermal Silastic implant (Uniplant) containing 55 mg (10%) of nomegestrol acetate. Fasting blood samples were drawn twice prior to implant insertion and then at the 1st, 3rd, 6th, and 12th months and every 6 months thereafter. Body weight increased from 54.9 kg at admission to 55.3 kg at 12 months of use (p 0.05) and to 56.0 kg at 24 months of use. Both systolic and diastolic blood pressure increased slightly at month 12 (p 0.01). Insulin, HbA1C, LDL-C, and GGT remained unchanged during 24 months of Uniplant use. A significant decrease in total cholesterol (p 0.05) was observed in the 3rd month, while a significant decrease in HDL-C (p 0.01) was observed only in the 6th month of Uniplant use. A significant increase in triglycerides (p 0.05) was observed only in the 12th month. Significant increases in fasting blood glucose levels (p 0.05 and p 0.01) were observed in the 3rd and 6th month, respectively, for 24 months of Uniplant use. Significant decreases in SGOT (p 0.05, p 0.01 and p 0.05) were observed in the 6th, 18th, and 24th months, respectively. A significant decrease in SGPT (p 0.05) was observed in the 18th month of Uniplant use. A significant increase in bilirubin (p 0.05) was observed only in the 3rd month of Uniplant use. Within the normal range, variation of fasting glucose was not correlated with changes in insulin levels and no clinical effects on lipoproteins, carbohydrate metabolism, insulin levels, and on hepatic function were observed in these women.

Differences in serum potassium concentrations in normal men in different geographic locations.

Hypokalemia has been associated with the taking of gossypol, a potential oral antifertility drug for men. Because the frequency of this response differed in different parts of the world, this study was done to learn if "normal" serum [K+] also differed. [K+] was measured by flame photometry in serum from apparently normal men from Austria (n = 30), China (53), Brazil (100), the Dominican Republic (38), and the US (103), and in plasma from Nigerian men (82). The mean (SD) for [K+] in Chinese men, 3.82 (0.27) mmol/L, was lower than that in Brazilians [4.06 (0.29) mmol/L], Austrians [4.14 (0.44) mmol/L], Dominicans [4.37 (0.33) mmol/L], or Americans [4.38 (0.37) mmol/L]. Apparently there are regional differences in average serum [K+], with men in China having lower serum [K+] than men elsewhere. This may predispose them to hypokalemia.

Guanine nucleotides and Ca2(+)-dependent lysosomal secretion in electropermeabilised human platelets.

1. Metabolically stable analogues of GTP, e.g. guanosine 5'-[gamma-thio]triphosphate (GTP[S]) and guanosine 5'-[beta,gamma-imido]triphosphate (pp[NH]pG), enhance the extent of Ca2(+)-dependent secretion of beta-N-acetylglucosaminidase and beta-galactosidase from electropermeabilised human platelets in the presence of less than 5 microM Ca2+. A similar effect is observed on addition either of 1,2-dioctanoin or of GTP in in the presence or absence of thrombin. 2. In the presence of higher Ca2+ concentrations the extent of enhancement of lysosomal secretion declines and little, or no, enhancement is observed at a [Ca2+] of 30-40 microM. Addition of leupeptin or antipain prevents this decrease in lysosomal secretion and enhances the extent of Ca2(+)-dependent lysosomal secretion obtained in the presence or absence of guanine nucleotides, thrombin or 1,2-dioctanoin. 3. The concentration of GTP[S] or pp[NH]pG required to obtain half-maximal enhancement of lysosomal secretion is dependent on [Ca2+] for secretion of 5-hydroxytryptamine, beta-N-acetylglucosaminidase and beta-galactosidase. At two fixed [Ca2+] the median effective concentration (EC50) values for GTP[S] and pp[NH]pG which characterise enhancement of 5-hydroxytryptamine secretion are significantly different from those characterising enhancement of the secretion of beta-N-acetylglucosaminidase and beta-galactosidase. 4. In the presence of a saturating concentration of GTP[S] marked 5-hydroxytryptamine and beta-N-acetylglucosaminidase secretion is observed at nanomolar [Ca2+] and these responses show little dependence on [Ca2+] over the attainable range. Secretion of beta-N-acetylglucosaminidase is also induced at nanomolar Ca2+ concentrations by addition of activators of protein kinase C. 5. Guanosine 5'-[beta-thio]diphosphate inhibits enhancement of beta-N-acetylglucosaminidase secretion induced by GTP[S] but has no effect on secretion of this enzyme induced by Ca2+ when added alone. 6. Our data provide some support for a model in which addition of metabolically stable guanine nucleotides enhances Ca2(+)-dependent platelet lysosomal secretion by activating a guanine-nucleotide-binding protein (GE) located close to the exocytotic site. However, not all the data are consistent with this postulate.

Calcium-dependent and calcium-independent exocytosis.

A large body of evidence supports the concept that calcium (Ca2+) plays a pivotal role in the control of exocytosis. However, recent experiments suggest that a rise in intracellular Ca2+ does not necessarily trigger secretion, and also that secretion can occur independently of cytosolic free calcium levels. This article briefly summarizes the early evidence that has formulated the role of Ca2+ in secretion, and then examines some of the recent evidence suggesting a Ca2+-independent mechanism of exocytosis.

Effect of thyroid status on the development of the different molecular forms of Na+,K+-ATPase in rat brain.

The effect of thyroid status on the postnatal development of the two molecular forms of Na+,K+-ATPase, distinguished kinetically on the basis of their ouabain sensitivity, was examined in rat brain. Hypothyroidism induced by PTU from day 1 postnatally significantly reduced the Na+,K+-ATPase activity in cerebellum (22-30 days) but not forebrain, whereas hyperthyroidism (T4 treatment from day 1) had no effect. The hypothyroidism-induced reduction in cerebellum was reflected by a 20-45% reduction in the activity of the alpha(+) form of Na+,K+-ATPase (high ouabain affinity) against control brains compared to a 60-70% reduction in the activity of the alpha form (low ouabain affinity). These results show that neonatally induced hypothyroidism leads to a selectively greater impairment of the ontogenesis of the activity of cerebellar alpha form of Na+,K+-ATPase. This may possibly reflect a retarded development of a selective cerebellar cell population containing predominantly the alpha form of the enzyme.