Star anise extracts modulation of reproductive parameters, fertility potential and DNA fragmentation induced by growth promoter Equigan in rat testes

ABSTRACT Equigan is an anabolic steroid that has been developed for veterinary use and derived from endogenous sex hormone testosterone that plays a key role in the development of male reproductive tissue as well as in puberty and spermatogenesis. The current study is aimed to investigate the possible prophylactic effect of star anise extracts (SAE) on the toxicity of rat testes, sexual hormones alternations, sperm count, sperm abnormalities and testicular DNA damage by Equigan. Forty adult male rats were equally divided into four groups (1st Control group, 2nd SAE group, 3rd Equigan and 4th Equigan+SAE group). Food and fluid intakes, relative body weight, potassium, chloride, phosphorous, non-progressive and immotile sperms were significantly increased in Equigan group as compared to control group. In contrast; relative testes weight, sodium, magnesium, total calcium, testosterone, FSH, LH, PRL, sperm count, progressive motility, and viability showed a significant decrease in Equigan group as compared to control groups. The relative weight of epididymis, seminal vesicles, prostates and serum calcium ions didn't change significantly in different studied groups. Co-administration of SAE with Equigan improved the sexual toxicity, electrolyte alternations, sperm count, abnormalities and DNA damage induced by Equigan.

Clinical behavior of a cohort of adult women with facial acne treated with combined oral contraceptive: ethinylestradiol 20 µg/dienogest 2 mg.

Acne vulgaris is the most common skin disease. It affects the young adult female population and generates great impact on physical and mental health. One of the treatments with good results for affected women is combined oral contraceptive pills (COCPs). The aim of this study was to determine the clinical effect of facial acne management with ethinylestradiol 20 µg/dienogest 2 mg in a cohort of Colombian adult women. A cohort of 120 female university students was followed for 12 months. These participants were enrolled in the Sexual and Reproductive Health Program of the Santiago de Cali University. This cohort admitted women between 18 and 30 years old who had chosen to start birth control with ethinylestradiol 20 µg/dienogest 2 mg COCPs, did not have contraindi cations to the use of COCPs, and had been diagnosed with acne. Monthly monitoring of facial acne lesion count was performed. Relative changes in facial lesion count were identified. At the end of follow-up, the percentage of reduction of lesions was 94% and 23% of women had a 100% reduction in acne lesions. In conclusion, the continued use of the ethinylestradiol 20 µg/dienogest 2 mg COCPs reduced inflammatory and non-inflammatory acne lesions in reproductive-age women between 18 and 30 years of age with no severe acne.

La reproducción asistida / Assisted reproduction

Introducción: dentro de las técnicas de reproducción asistida de baja tecnología está la inseminación intrauterina, donde se colocan los espermatozoides dentro del útero de una mujer cerca del momento de la ovulación. Presentación del caso: se presenta el caso de una paciente de 31 años de edad, color de piel blanca, de procedencia rural (municipio Minas de Matahambre, Pinar del Río, Cuba) con el único antecedente personal de infertilidad secundaria y obstétrico de gesta 1, parto 0, aborto 1 a los 18 años, con DIU T de cobre por nueve años para lo cual fue atendida junto a su pareja en la consulta de infertilidad del policlínico universitario "Hermanos Cruz" de Pinar del Río, donde se le diagnosticó trastornos de ovulación e infección vaginal y una oligoastenospermia con varicocele izquierdo a su pareja, para lo cual llevaron tratamiento médico quirúrgico combinado. Conclusión: se logró primero la varicocelectomía y espermatogénesis con merapur (HMG), la ovulación con HMG y clomifeno, luego se realizó una fertilización de baja tecnología, con lo que se logró un embarazo, que llegó a feliz término a las 41 semanas de gestación. Por lo riesgoso de este tipo de embarazo y el resultado feliz que tuvo, se decidió publicar el caso.

Introduction: among assisted reproduction techniques of low technology is intrauterine insemination, where sperm is placed in the uterus of a woman near the time of ovulation. Case report: the case of a female 31-year-old patient, white skin, of rural origin (Minas de Matahambre Municipality, Pinar del Rio, Cuba) presents for the sole personal history of secondary infertility and obstetric geostation 1, delivery 0, abortion 1 to 18, with Copper T IUD for nine years for which she was served with her partner in the office of infertility at Hermanos Cruz university polyclinic of Pinar del Rio, where she was diagnosed disorders ovulation and vaginal infection and her partner with a left varicocele oligoasthenospermia, which led to combined surgical treatment. Conclusion: varicocelectomy was first achieved and spermatogenesis with merapur (HMG), ovulation with HMG and clomiphene, and then a low-tech fertilization took place, bringing a pregnancy, which came to fruition at 41 weeks of gestation was achieved. So this kind of risky pregnancy and was happy result, it was decided to publish the case.

Medical termination of pregnancy.

PIP: This review focuses on advances in the medical termination of pregnancy during the early period of the first trimester, when most abortions are performed. The drugs are used to terminate pregnancy act by inhibiting the synthesis of progesterone, inducing myometrial contractions, antagonizing the action of progesterone, or inhibiting trophoblast development. Among the drugs used in medical abortion are epostane, prostaglandins (including misoprostol and gameprost), combined methotrexate and misoprostol, tamoxifen-misoprostol regimen, mifepristone and prostaglandin, and antiprogestin and prostaglandins. The efficacy, side effects, and contraindications of these drugs in the medical termination of pregnancy are discussed. In general, medical abortion is associated with higher rates of prolonged bleeding, nausea, vomiting, and pain as compared to surgical abortion. However, medical termination of pregnancy has a high rate of efficacy in women with early pregnancies. In addition, medical abortion is safe and acceptable to women, and it does not require anesthesia. Lastly, women who choose medical abortion must have access to a center where suction curettage is available, should heavy bleeding occur and blood transfusion is required.^ieng

Minimal stimulation IVF using clomiphene citrate and oral contraceptive pill pretreatment for LH suppression.

OBJECTIVE: To determine if oral contraceptive pill (OC) pre-treatment prior to minimal stimulation IVF using clomiphene citrate (CC) would make the procedure easier to perform by preventing the LH surge and result in pregnancy rates (PRs) comparable to stimulated IVF. DESIGN: Prospective cohort study. SETTING: Private tertiary infertility center. PATIENT(S): Thirty-two women with tubal or pelvic adhesive disease as the cause of their infertility, ovulatory cycles, under the age of 40, and no male factor. INTERVENTION(S): Two-month ovarian-hypothalamic-pituitary axis suppression with OC followed by CC 100 mg on day 3 of the cycle for 8 days, hCG administration midcycle, follicle aspiration, IVF, and embryo transfer. MAIN OUTCOME MEASURE(S): Oocytes retrieved, serum LH and estradiol levels, maturity of oocytes, fertilization rates, embryo number and quality, and PRs. RESULT(S): Thirty-six patients completed 71 stimulation cycles and 64 follicle aspirations. No LH surges occurred with a mean mature oocytes retrieved of 3.2, 90% fertilization rate, and mean 2.5 embryos transferred. Twenty-one of the 64 cycles resulted in a clinical pregnancy (32.8% PR per retrieval) with 2 other biochemical pregnancies and 3 twin gestations. This was not significantly different from the matched cohort stimulated IVF. CONCLUSION(S): Minimal stimulation IVF is a simple, low-cost, and low-risk alternative to stimulated IVF with comparable PRs.

PIP: This prospective cohort study examines the efficacy of minimal stimulation IVF (in vitro fertilization) using clomiphene citrate (CC) and oral contraceptive (OC) pretreatment for luteinizing hormone (LH) suppression in comparison with stimulated IVF. About 32 women with tubal or pelvic adhesive disease as the cause of their infertility, ovulatory cycles, aged under 40 years, and with no male factor attending a private tertiary infertility center were included in the study. These subjects received a 2-month ovarian-hypothalamic-pituitary axis suppression with OC, followed by CC 100 mg on day 3 of the cycle for 8 days, human chorionic gonadotropin administration midcycle, follicle aspiration, IVF, and embryo transfer. After 71 stimulation cycles and 64 follicle aspirations on 36 patients, it was observed that no LH surges occurred, with a mean number of mature oocytes retrieved of 3.2, a 90% fertilization rate, and a mean of 2.5 embryos transferred. About 21 of the 64 cycles resulted in clinical pregnancy (32.8% pregnancy rate per retrieval) with 2 biochemical pregnancies and 3 twin gestations. Results were insignificantly different from the matched cohort stimulated IVF. The study confirms the efficacy of OC use for ovarian-hypothalamic-pituitary axis suppression followed by minimal stimulation IVF using CC as a simple, low-cost and low-risk alternative to stimulated IVF with comparable pregnancy rates.

Tamoxifen compared to methotrexate when used with misoprostol for abortion.

The purpose of this study was to compare tamoxifen to methotrexate, with respect to effectiveness, when followed by misoprostol to induce abortion. In the first phase, 198 women presenting for medical abortion at < 7 weeks gestation were randomized to receive either 40 mg of tamoxifen, followed 2 to 3 days later by 800 micrograms of misoprostol self-administered vaginally or 50 mg/m2 of methotrexate, followed 5 to 7 days later by the same dose of misoprostol. In the second phase, 200 women were randomized to receive 20 mg tamoxifen twice daily for 4 days, followed by 800 micrograms misoprostol or the same regimen of methotrexate and misoprostol as in phase 1. The main outcome measure was success rate determined by the number of women who aborted without surgery. In phase 1, the success rate was higher in the methotrexate group (93.0%) compared to the tamoxifen group (85.7%) (p = 0.045). In the tamoxifen group, nine of 98 women had incomplete abortions with symptoms requiring a surgical aspiration, compared to one of 100 women in the methotrexate group. In phase 2, the success rates were 90.9% in the methotrexate group compared to 84.7% in the tamoxifen group (p = 0.20). The side effects were less in the tamoxifen group in phase 1 but not in phase 2. When tamoxifen is given as a single dose, it is less effective than methotrexate but when it is given 20 mg twice daily for 4 days, there is no significant difference. Tamoxifen does not appear to have any benefits over methotrexate.

PIP: This study aims to compare the effectiveness of tamoxifen with that of methotrexate when each is used in combination with misoprostol for abortion. In the 1st phase of the study, 198 medical abortion cases at 7 weeks gestation were randomized to receive either 40 mg of tamoxifen followed by 800 mcg of misoprostol after 2-3 days or 50 mg/sq. m of methotrexate followed by the same dose of misoprostol after 5-7 days. In the 2nd phase, 20 mg tamoxifen twice daily for 4 days was administered to 200 women, followed by 800 mcg misoprostol or the same methotrexate and misoprostol regimen as in phase 1. The number of women who experienced abortion without surgery was determined to measure the success rate. The success rate in phase 1 was higher in the methotrexate group (93.0%) than in the tamoxifen group (85.7%) (p = 0.045). About 9 in 98 women in the tamoxifen group and 1 in 100 women in the methotrexate group had incomplete abortions, indicating surgical aspirations. In the 2nd phase, the success rates were 90.9% in the methotrexate group and 84.7% in the tamoxifen group (p = 0.20). There were fewer side effects in the tamoxifen group during the 1st phase but not in the 2nd phase. Tamoxifen was seen to be less effective than methotrexate if given in a single dose. There was no significant difference when tamoxifen was given in 20 mg doses twice daily for 4 days. There were no advantages observed in tamoxifen over methotrexate.

A comparison of tamoxifen and misoprostol to misoprostol alone for early pregnancy termination.

A study was undertaken to determine whether the combination of oral tamoxifen and moistened misoprostol administered vaginally was superior to that of placebo and moistened misoprostol administered vaginally for elective termination of early pregnancies.A clinical trial was conducted with a study group of 150 healthy women with pregnancies of

Anti-implantation activity of antiestrogens and mifepristone.

To develop a better postcoital contraceptive, the following antiestrogens were tested for their anti-implantation activity in the rat: anordrin, anordiol, tamoxifen, ICI 182,780, and RU 39411. The compounds were administered orally or subcutaneously (s.c.) to female rats on days 1, 2, and 3 of pregnancy. All the antiestrogens tested were 100% effective in preventing blastocyst implantation. The lowest effective doses when administered orally were 10, 1.25, 0.062, 6.0 (partially effective), and 0.01 mg/kg/day, respectively. The estimated median effective doses (ED50) were 5.60, 0.40, 0.035, 5.40, and 0.0074 mg/kg/day, respectively. When administered s.c., the minimum effective doses in preventing blastocyst implantation in all animals were 2.0, 0.1, 0.1, 0.1, and 0.01 mg/kg/day, respectively. Anordrin, anordiol, and ICI 182,780 were more potent when administered s.c.; whereas tamoxifen and RU 39411 were effective at similar doses when administered parenterally or orally. RU 39411 was the most potent among the antiestrogens tested and should be evaluated as a potential postcoital contraceptive. The administration of mifepristone, an antiprogestin, at a dose of 8 mg/kg/day blocked blastocyst implantation in all treated animals; whereas at a dose of 4 mg/kg/day or lower, the drug was ineffective. These findings confirm that estradiol and progesterone are essential for blastocyst implantation in the rat. The capacity of mifepristone to potentiate the anti-implantation activity of the antiestrogens was also determined. The combination of a non-effective dose of each of the antiestrogens (anordrin, anordiol, and tamoxifen), and RU 39411, with mifepristone at a non-effective dose, prevented pregnancy, demonstration that an antiprogestin and antiestrogen act synergistically in blocking blastocyst implantation in the rat. The antiestrogen compounds whose anti-implantation activities were potentiated by mifepristone were found to possess significant estrogenic activity, when assayed by measuring the increase in the uterine weights of ovariectomized rats. The only exception was ICI 182,780, which showed no estrogenic activity in the uterine weight bioassay and did not act synergistically with mifepristone in blocking blastocyst implantation. Estradiol was effective in preventing pregnancy at a dose of 1 microgram/kg/day. The combination of non-effective doses of estradiol and mifepristone did not prevent pregnancy. The findings that mifepristone potentiates the anti-implantation activity suggests that the synergistic effect may be a unique property of this class of antiestrogens.

PIP: In New York, female and male rats copulated on the afternoon of proestrus as part of a study aiming to determine whether antiestrogens alone or in combination with mifepristone (RU-486) will block blastocyst implantation in the rat. This study is part of research efforts to develop a better postcoital contraceptive. The antiestrogens included RU39411; ICI 182,780; anordrin; anordiol; tamoxifen; and estradiol. The laboratory researchers treated the rats orally or subcutaneously on days 1, 2, and 3 of pregnancy. They killed them on day 8-9 to examine the uteri for the presence or absence of implanted embryos. All the antiestrogens effectively prevented blastocyte implantation. Using the measurement mg/kg/day, the lowest effective oral dose was 10 for anordrin; 1.25 for anordiol; 0.062 for tamoxifen; 6 (80% effective) for ICI 182,780; and 0.01 for RU 39411. These antiestrogens' estimated median effective doses were 5.6, 0.4, 0.035, 5.4, and 0.0074 mg/kg/day, respectively. In all animals, the minimum effective doses administered subcutaneously were 2, 0.1, 0.1, 0.1, and 0.01 mg/kg/day, respectively. Anordrin, anordiol, and ICI 182,780 were more effective during subcutaneous administration while tamoxifen and RU 39411 were as effective at similar doses during parenteral or oral administration. The most potent antiestrogen was RU 39411. This antiestrogen should be evaluated as a potential postcoital contraceptive. An 8 mg/kg/day dose of RU-486 blocked blastocyst implantation in all rats. The 4 mg/kg/day dose was completely ineffective. RU-486 augmented the activity of anordrin, anordiol, tamoxifen, and RU39411 synergistically, resulting in prevention of pregnancy at non-effective doses of RU-486 and the antiestrogens. These same antiestrogens also exhibited significant estrogenic activity as determined by an increase in uterine weights of ovariectomized rats. Estradiol prevented pregnancy at a dose of 1 mcg/kg/day. RU-486 did not potentiate estradiol. These findings suggest that the synergistic effect of anordrin, anordiol, tamoxifen, and RU39411 may be unique to these antiestrogens.

Sex preselection through albumin separation of sperm.

OBJECTIVE: To determine if passage of sperm through columns of liquid albumin before their use in artificial insemination could affect the sex ratio at birth. DESIGN: Sperm were isolated by layering over columns of liquid albumin. The isolated fractions were inseminated into the uterus on the presumptive day of ovulation. SETTING: Patients were treated in 65 clinical practices (Sperm Centers) located both in this country (57) and abroad (8). PATIENTS: Individuals were self-selected by their desire to have a child of a specified sex. MAIN OUTCOME MEASURE: The sex of offspring resulting from the insemination of isolated sperm. RESULTS: Insemination with sperm isolated to enhance male sex preselection produced 71% and 76% males depending on the technique. Use of isolated sperm in women who were taking clomiphene citrate was associated with a 69% birth of females. CONCLUSIONS: Separation of sperm on columns of liquid albumin can affect the sex ratio at birth.

PIP: Fertility specialists examined data on 1407 births resulting from artificial inseminations with sperm separated on albumin columns and occurring at 59 sperm centers in the US and at 8 sperm centers in other countries to determine whether albumin separation can effectively affect the sex ratio. The patients had already had at least 2 children of the same sex and wanted a child of the opposite sex and consciously opted to use sex preselection techniques. Male newborns predominated (72% vs. 28%). The modified protocol 3 resulted in a higher percentage of male births than did protocol 3 (76% vs. 71%), but the difference was insignificant. Both protocols significantly influenced the sex ratio (71% vs. 29% for protocol 3, and 76% vs. 24% for modified protocol 3; p .0001). For female sex preselection, protocol 2 included administration of clomiphene citrate to the woman to induce ovulation and less complete sperm separation. It resulted in a significantly higher percentage of female births than male births (69% vs. 31%; p .0003). 5.7% of a representative sample (sperm centers in Dallas, Texas, and Lathrup Village, Michigan) were lost to follow-up, but these 547 couples were apparently the same as the entire sample. These findings indicated that the albumin separation method does influence the sex ratio at birth, but its use is likely limited since it is not 100% effective.

Effect of tamoxifen alone and in combination with RU 486 on the endometrium in the mid-luteal phase.

The effects of RU 486 combined with tamoxifen and tamoxifen alone on hormonal parameters and endometrial development at the time of implantation were studied. Measurements of cytosolic oestrogen and progesterone receptors in endometrium and placental protein 14 (PP14) in plasma were also included. Three dosage schedules were used: single oral dose of 40 mg tamoxifen alone and in combination with 200 mg RU 486, and 40 mg tamoxifen for three consecutive days starting on the first day after the luteinizing hormone (LH) surge. The combined treatment prolonged the luteal phase (P < 0.05) and increased the plasma levels of progesterone. A single dose of tamoxifen did not affect the bleeding pattern and plasma hormone levels, but raised plasma oestradiol and LH with the 3-day treatment. The endometrium was retarded after the combined and the 3-day treatment with tamoxifen. Concentrations of cytosolic progesterone receptors were higher after the combined therapy, but were unaffected after tamoxifen only. PP14 levels were higher (P < 0.05) after repeated tamoxifen doses than in controls, but were lower with combined treatment. Progesterone and oestrogen are evidently necessary for endometrial maturation during the secretory phase of the menstrual cycle. PP14 levels in plasma cannot be used for clinical assessments of endometrial function because high levels coincide with disturbed endometrial development.

Effects of hormone therapy on the endometrium.

Hormone therapy induces a variety of histologic changes in the endometrium. Histologic patterns encountered in the most commonly used hormonal regimens are described. Oral contraceptives are associated with inactive, atrophic, or pseudosecretory glands and edematous stroma, decidual reaction without spiral arterioles, and stromal granulocytes. A high-potency progesterone may induce marked stromal and vascular hyperplasia and stromal myomatous nodules. Ovulation induction therapy accelerates the maturation of the stroma and is often associated with a discrepancy between the glands showing early secretory changes and an edematous, decidualized stroma. Hormone replacement therapy may stimulate endometrial proliferation if estrogens are used alone and produce endometrial hyperplasia and neoplasia. When estrogen and progesterone regimens are used, a wide range of histologic pattern may be found in various combinations: proliferative and secretory endometrium, glandular and adenomatous hyperplasia, stromal hyperplasia and decidual transformation, glandular metaplasia, atrophic endometrium, and any of the above with endometrial atrophy. Progesterone therapy for endometrial hyperplasia and neoplasia is followed by secretory changes of the endometrium, mostly subnuclear vacuoles, decidual reaction, and sometime squamoid "morules." Secretory changes seen after progesterone therapy in the endometrium do not rule out residual carcinoma. For hormone therapy for breast carcinoma, tamoxifen acts as an antiestrogen on the breast but often acts as an estrogen agonist on the endometrium; tamoxifen therapy may be associated with endometrial hyperplasia, polyps, adenomyosis, adenomatous hyperplasia, and adenocarcinoma.

PIP: Steroid sex hormones cause immediate changes in the endometrium. The histologic effect depends on the hormone, the potency, dosage, and the host receptor status. Oral contraceptives (OCs) containing a low-dose, low-potency progesterone and low-dose estrogen stop proliferation of the glands during the 1st few cycles and the glands are straight and unevenly distributed, with considerable stroma between them. The minimal secretory features of the glands disappear with longterm use of these OCs, resulting in complete atrophy of the glands and of the stroma. These OCs also cause decidual reaction without spiral arterioles and stromal granulocytes. OCs with high potency progesterone cause distinct hyperplasia of the endometrial stroma and vessels, atrophy of the glands, and stromal myomatous nodules. Ovulation induction therapy consists of various combinations of some drugs (clomid, human menopausal gonadotropins, gonadotropin-releasing hormone, and human chorionic gonadotropin). This therapy accelerates secretory changes in the stroma, resulting in enhancement of the endometrial maturation process. It makes it difficult to differentiate between glands displaying early secretory changes and an edematous, decidualized stroma. Hormone replacement therapy using estrogens and progesterone cause different histologic patterns, including stromal hyperplasia and decidual transformation, glandular and adenomatous hyperplasia, glandular metaplasia, proliferative and secretory endometrium, atrophic endometrium, and any of these with endometrial atrophy. Progesterone therapy for endometrial hyperplasia and neoplasia produces secretory changes of the endometrium, such as subnuclear vacuole, decidual reaction, and squamoid "morules." These changes can result in residual carcinoma. Tamoxifen therapy for breast cancer is linked with endometrial hyperplasia, polyps, adenomyosis, adenomatous hyperplasia, and adenocarcinoma.

Combined effects of RU486 and tamoxifen on the growth and cell cycle phases of the MCF-7 cell line.

The antiproliferative effect of RU486 and its effect combined with tamoxifen on the growth and cell cycle kinetics parameters on the MCF-7 human carcinoma cells were investigated. When MCF-7 cells in the exponential growth phase were treated with RU486 (10(2) nmol/L), a time-dependent cell growth inhibition was observed which was significant 5 days after the beginning of treatment. This inhibition was accompanied by a time- and dose-dependent decrease in the percentage of S and G2-M phase cells and a concomitant increase in the percentage of cells in the G0/G1 phase of the cell cycle. With tamoxifen (10(5) pmol/L), growth inhibition was obtained after 4 days of treatment of cells, and the blockage of the cell cycle occurred in the G0/G1 phase. In the case of simultaneous treatment of MCF-7 cultures with RU486 (10(2) nmol/L) and tamoxifen (10(5) pmol/L), we observed a synergistic inhibitory effect on the proliferative rate for short treatment (less than or equal to 3 days), whereas RU486 or tamoxifen alone had no effect. For the intermediate treatment (4 days), the combined effect of RU486 and tamoxifen was not significant compared to the effect of tamoxifen alone. For the long treatment (greater than 4 days), there were no differences between the number of cells in the treated cultures under different experimental conditions, but all were inhibited compared to those in control cell cultures. This simultaneous treatment of cells does not induce any change in the distribution of cells in the different cell cycle phases compared to tamoxifen percentages. These results suggest that RU486 is a cell cycle phase-specific growth inhibitory agent, and a combination of antiestrogen/antiprogestin should be considered as a possible improvement in breast cancer endocrine therapy.

PIP: The antiproliferative effect of the antiprogestational agent RU-486 (100 nmol/L), alone and its additive effect in combination with the antiestrogenic tamoxifen (100,000 pmol/L) on the growth and cell cycle phases of the human breast cancer cell line MCF7, which is ER and PR positive, using image cytometry was investigated. On days 2, 3, 4, 5, 7, and 9, cells were harvested from control and RU-486-, tamoxifen, and RU-486- and tamoxifen-treated cultures and counted with an hemocytometer. Cell number increased in the RU-486-treated culture for the first 4 days as well as in the control culture. RU-486 treatment of cells for 5 days produced a significant time-dependent cell growth inhibition (P 0.01) compared with that in the control cells. With tamoxifen (100,000 pmol/L), growth inhibition was obtained after 4 days of treatment of cells, and the blockage of the cell cycle occurred in the G0.G1 phase. For the short treatment a significant synergistic growth inhibition (P 0.05 and P 0.01 on days 2 and 3, respectively) compared to RU-486 or tamoxifen alone, which had no effect compared to control cells. In the case of simultaneous treatment of MCF7 cultures with RU-486 (100 nmol/L) and tamoxifen (10000 pmol/L), a synergistic inhibitory effect of the proliferative rate was not produce an effect. During intermediate treatment (4 days), the combined effect of RU-486 and tamoxifen was not significant compared to the effect of tamoxifen alone. On the other hand, tamoxifen inhibited growth compared to that in control cells (P 0.05). These findings suggest that RU-486 is a cell cycle phase-specific growth inhibitory agent, and a combination of antiestrogen and antiprogestin agents may be of possible use in breast cancer endocrine therapy.

Selected aspects of polycystic ovarian disease.

Although there is general agreement about the polycystic ovary as an anatomic entity, a classic description of an associated syndrome remains elusive. This lack of definition, however, has not impeded clinical investigation. This article focuses on the diagnosis, pathogenesis, hypotheses, and treatment of polycystic ovarian disease.

PIP: Ultrasonography provides physicians much information for the epidemiology and diagnosis of polycystic ovarian disease (PCOD)--a yet to be defined associated syndrome. For example, some physicians used it to reveal that 92% of women with hirsutism and regular menstrual cycles had PCOD. Considerable research exists on the link between insulin resistance. PCOD, and hyperandrogenism. Some results confirm the link while others do not. Abnormal gonadotropin dynamics are 1 of the most consistent characteristics of PCOD. Researchers have conceived various hypotheses for PCOD. A long-lived hypothesis is that elevated estrone levels which occur regularly in PCOD increase the sensitization of pituitary luteinizing hormone (LH) secretion and reduces secretion of follicle stimulating hormone to the gonadotropin releasing hormone stimulus. Another hypothesis is that progesterone deficiency facilitates PCOD. Various PCOD treatments exist. Physicians have treated PCOD with clomiphene citrate or nighttime small doses of corticosteroids for 20-30 years. Recent observations indicate the dexamethasone has a longer half life than prednisone or prednisolone. Since almost 50% of women with PCOD are obese, weight reduction has beneficial effects. Administration of progesterone is a possible treatment that is often ignored. Several clinical studies have included administration of bromocriptine to women with PCOD since a sizable number of such women have high levels of prolactin indicating a possible dopamine deficiency. The studies with bromocriptine have not showed much promise. Evidence suggests that administering oral contraceptives to premenopausal women with PCOD may reduce their risk of later developing ovarian cancer. Gonadotropin and gonadotropin releasing hormone therapies are possible means of inducing ovulation in PCOD women. Various physicians have used laparoscopy to apply different techniques to induce ovulation in women with PCOD. These techniques included sharp puncture, electric current, and laser vaporization or endocoagulation of the cysts.

Delayed interval delivery of two remaining fetuses in quintuplet pregnancy after embryo reduction: report and review of the literature.

A case report is presented with a prolonged interval between delivery of 25 days. A quintuplet pregnancy resulted from hormonal stimulation of ovulation. Two fetuses remained after an embryo reduction was performed at 11 weeks gestation. At 22.5 weeks gestation the first twin (310 g) was delivered after spontaneous rupture of membranes. Using tocolytic agents, the second twin (710 g) was born at 26 weeks of gestation. This case is discussed and a review of the literature is given.

PIP: In Holland, infertility specialists at Sophia Hospital in Zwolle administered human menotropins chorionic gonadotropin injections to a 26-year old woman to induce ovulation. Donor artificial insemination resulted in conception. At 8 weeks gestation, ultrasonography revealed 5 fetuses. Since quintuplet pregnancies increase the risk of maternal complications and of perinatal morbidity and mortality, she consented to embryo reduction at 11 weeks gestation, resulting in a twin pregnancy. Between 16-18 weeks gestation, she had some vaginal bleeding. At 22.5 weeks gestation, she suffered lower abdominal pain and fluid loss and delivered a 310 fm female who died within a few hours. The physicians ligated the umbilical cord with vicryl near the cervix. The gestational sac of twin B was sticking out of the internal ostium, but she did not deliver twin B. There were no signs of placental separation or of infection. The woman and her husband agreed to postpone delivery of the 2nd fetus. She remained in bed while receiving iv tocolytic drugs (ritodrine R). The physicians also administered iv antibiotics for 3 days (ampicilline and cefotaxim). Weekly ultrasound examination showed that twin B grew normally. A subfebrile temperature and an increase in the white blood cell count resulted in restart of antibiotic therapy. Health workers gave her intramuscular injections of betamethasone to accelerate development of the fetus' lungs at 26 weeks. 2 days later, she went into labor. The physicians ruptured the membranes and delivered a 710 gm male newborn. She later delivered 3 intact amniotic sacs with autolytic fetuses. She recovered uneventfully. The newborn eventually developed bronchopulmonary dysplasia and dies at 3 months. None of the 1st-born infant in 14 delayed interval delivery cases reported in the literature since 1957 survived. 13 of the 17 later born infants did survive. Tocolytic agents were used to postpone delivery in 10 cases. Cervical cerclage was done in the 7 other cases. All but 1 case received broad-spectrum antibiotics.

Can we prevent breast cancer?

PIP: After introducing reasons why prevention of breast cancer is needed, this proposal for preventing breast cancer with the drugs tamoxifen and gestodene is presented. Improvements in treatment of breast cancer by local surgery and adjuvant therapy can be expected to be modest at best. Screening may prevent some deaths, but is not cost effective, since the majority of cancer patients will still die. The hope of preventing breast cancer with a low fat diet is still unproven, and epidemiologic evidence so far suggests that long-term diets with 20% fat, probably taken during youth, are needed. Much more likely to be successful is formulating an oral contraceptive, and/or a post-menopausal estrogen supplement, with a steroid that prevents breast cancer. There is evidence that the new progestogen gestodene inhibits growth of breast neoplastic cells. It may work during the progression of neoplasm, displace estradiol from the cancer cell estrogen receptor, and cause breast cancer cells to secrete the negative growth modulator called TGF beta. The anti-estrogen *tamoxifen is another agent that may prove useful in preventing breast cancer. It is cytostatic for tumor cells, inhibits initiation and promotion of cancer growth, is an effective palliative treatment for existing cancer in post-menopausal women, and may even raise high-density lipoprotein cholesterol. More work needs to be done on tolerance of side effects, its biological effects on coagulation, lipid and bone metabolism, psychological and sexual consequences and its effect on cancer in pre-menopausal women. The ethics and feasibility of designing clinical trials of these drugs are discussed.^ieng

[Can breast cancer be prevented?]. / Kan brystkreft forebygges?

More than six-fold variation in incidence between countries, an increasing incidence among immigrants to high incidence areas, and a general increase in the incidence of breast cancer within countries, are factors which suggest a potential for prevention. Reproductive factors such as early menarche, late age at first full term birth, nulliparity, and late age at menopause increase risk of breast cancer, but manipulation of any one of these factors does not seem to be a realistic preventive tool. Nevertheless, the future possibility of using tamoxifen as a chemopreventive agent against breast cancer is discussed, particularly in relation to women at increased risk due to familial clustering. Alcohol consumption by young women, and overweight among postmenopausal women may also increase the incidence of breast cancer. Consequently, reduced alcohol intake by young women, and weight reduction among overweight women after menopause may reduce the risk of breast cancer.

PIP: In 1980, there were 570,000 cases of breast cancer in the world. In Norway, there are an average of 2000 new cases per year, and incidence had increased 50% from 1955 to 1984. About 40% of those afflicted die of the disease. Environmental, age, and reproductive factors seem to be implicated in its genesis. The rate increased almost fivefold in the course of a generation among Polish people who migrated to California from low incidence areas. It doubled among Chinese and Japanese who moved to California. The rate increases sharply up to age 50, then it levels off, thus early menopause is protective. Ovarial hormones (estrogen and progesterone) play a role in the development of preclinical tumors. Younger age at first delivery offers protection, but women who give birth to their first child after age 35 face a higher risk than nulliparas. Women with early menarche, which can be delayed by a lower caloric intake and vigorous physical activity, also face a heightened risk. Before menopause, overweight women are relatively protected, but the reverse is true after age 60. The consumption of animal fat is another risk factor, although a US study that involved 90,000 nurses did not bear this out. The Japanese increased their intake of animal fat from 10-25% from 1955-1975 without a corresponding increase in the rate of breast cancer. A vegetarian diet is nonprotective. Even the moderate consumption of alcohol increases the risk by 40% for women aged 15-30. Long-term use of oral contraceptives before birth of the first child up to age 35 increases the risk. Tamoxifen has protected women with a familial history of breast cancer who face a 3-5 fold higher risk. After menopause, its estrogenic properties promote the risk. Tamoxifen has an antitumor effect that can treat tumors clinically which are not manifested; it also lowers LDL (low density lipoprotein) and increases HDL (high density lipoprotein) cholesterol.

Infertility: a health problem in the Muslim world.

PIP: Between November 1980-August 1989, physicians in Cairo, Egypt followed 1488 infertile couples. The study reported the extent of infertility, its etiology, and problems related to its management. Primary and secondary infertility affected 70.7% and 29.3% of the couples, respectively. Length of infertility ranged from 1 to 23 years (mean = 7.18 for primary infertility and 6.05 for secondary infertility). 306 husbands (20.6% of the couples) had either an insufficient sperm count (20 X 1 million), insufficient sperm motility (40%), or 40% abnormal sperm. Both the husband and wife of 181 couples (12.2%) suffered from infertility. The physicians could not identify the cause of infertility in 49 couples (3.3%). 952 wives (64% of the couples) were infertile. Tubal problems were mainly responsible for female infertility (42%) followed by ovulatory disorders (25.3%), multiple factors (23.4%), pelvic endometriosis (5.6%), and cervical effects (4.2). Various treatments included laparoscopic adhesiolysis in 30 patients, tubal microsurgery in 523 patients, induction of ovulation and monitoring (e.g., clomid and HCG) in 224 patients, in vitro fertilization (IVF) and embryo transfer (ET) in 256 patients, artificial insemination with husband's capacitated sperm along with ovulation induction in 114 couples, intrauterine synechia and septa via hysteroscopy in 17 patients, and abdominal myomectomy in 57 patients. The follow-up pregnancy rate for 523 microsurgery patients was 55.2% and 38% went full term. Only 51-63% of the couples could afford to pay for IVF and ET, induction/monitoring of ovulation, or artificial insemination with husband's sperm all of which only the private sector provided. Patients had to wait for laparoscopy and microsurgery which were also available through government hospitals. These results demonstrate that prevention of infertility is preferable to treatment particularly in developing countries such as Egypt. Islam's view of infertility and family is also addressed.^ieng

Fertility after contraception or abortion.

There is a very small correlation, if any, between the prior use of OCs and congenital malformations, including Down's syndrome. There are few, if any, recent reports on masculinization of a female fetus born to a mother who took an OC containing 1 mg of a progestogen during early pregnancy. However, patients suspected of being pregnant and who are desirous of continuing that pregnancy should not continue to take OCs, nor should progestogen withdrawal pregnancy tests be used. Concern still exists regarding the occurrence of congenital abnormalities in babies born to such women. The incidence of postoperative infection after first trimester therapeutic abortion in this country is low. However, increasing numbers of women are undergoing repeated pregnancy terminations, and their risk for subsequent pelvic infections may be multiplied with each succeeding abortion. The incidence of prematurity due to cervical incompetence or surgical infertility after first trimester pregnancy terminations is not increased significantly. Asherman's syndrome may occur after septic therapeutic abortion. The pregnancy rate after treatment of this syndrome is low. The return of menses and the achievement of a pregnancy may be slightly delayed after OCs are discontinued, but the fertility rate is within the normal range by 1 year. The incidence of postpill amenorrhea of greater than 6 months' duration is probably less than 1%. The occurrence of the syndrome does not seem to be related to length of use or type of pill. Patients with prior normal menses as well as those with menstrual abnormalities before use of OCs may develop this syndrome. Patients with normal estrogen and gonadotropin levels usually respond with return of menses and ovulation when treated with clomiphene. The rate for achievement of pregnancy is much lower than that for patients with spontaneous return of menses. The criteria for defining PID or for categorizing its severity are diverse. The incidence of PID is higher among IUD users than among patients taking OCs or using a barrier method. The excess risk of PID among IUD users, with the exception of the first few months after insertion, is related to sexually transmitted diseases and not the IUD. Women with no risk factors for sexually transmitted diseases have little increased risk of PID or infertility associated with IUD use. There appears to be no increased risk of congenital anomalies, altered sex ratio, or early pregnancy loss among spermicide users. All present methods of contraception entail some risk to the patient. The risk of imparied future fertility with the use of any method appears to be low.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: This is a comprehensive review of the risk of infertility or adverse effects on pregnancy outcome, such as chromosomal or congenital birth defects, amenorrhea, pelvic inflammatory disease (PID), or spontaneous abortion, after use of oral contraceptives, IUDs, induced abortion or spermicides. The sequelae reported for orals are chromosomal abnormalities, the VACTERL anomalies, masculinization of female fetus, Down's syndrome and post-pill amenorrhea. Several large studies found no increased risks for birth defects, although the risk of malformations when pregnant women inadvertently take the pill in early pregnancy was high in 1 of 2 such studies. Masculinization was reported with high dose combined hormone treatment and in 2 infants of a woman who took Enovid. the bulk of recent studies on secondary amenorrhea indicate that it is rare, but just as likely to occur in women with prior normal or abnormal menstrual patterns. One study found that amenorrhea is 7.7 times more likely to develop in women who took the pill to regulate menses. It is recommended that women with amenorrhea be screened for pituitary tumors and counseled before prescribing pills, and that those who fail to ovulate after stopping the pill be treated at least 6 months with clomiphene. A massing of all studies on the impact of 1st trimester induced abortion on subsequent fertility, premature delivery and spontaneous abortion, shows all relative risks around 1.0. After multiple abortions, the results are conflicting. In contrast, prior series analyzing illegal abortion have an unquestioned adverse effect on fertility and pregnancy outcome. Asherman's syndrome, a rare disorder of intrauterine adhesions, menstrual abnormalities, infertility and habitual abortion, has been associated with D & C abortion concurrent with pelvic sepsis, or traumatic pregnancy with D & C. This condition can be treated with moderate success. The bulk of IUD studies conclude that there is no overall decrement in fertility, while some disaggregated studies point the Dalkon shield as a higher risk and copper IUDs as a lower risk. PID and its consequences are now considered related to the immediate post-insertion time frame, or specifically to women who are at risk of contracting sexually transmitted disease, i.e., those with multiple partners, those with prior PID and nulliparas. Comprehensive review of current large series on spermicides shows no relationship between their use and spontaneous abortion or congenital malformation.

Regulation of non-pregnant human uterine contractility. Effect of antihormones.

Uterine contractility was recorded on cycle day LH+6 to LH+8 in a control and treatment cycle in 14 healthy non-pregnant volunteers. In the treatment cycle the subjects received either 50 mg of the antiprogestin RU 486 daily for three days or 40 mg of the anti-estrogen tamoxifen daily for two days. The treatment started on day LH+2. During the recording, 2 to 5 micrograms PGF2 alpha was administered into the uterine cavity. The plasma levels of progesterone and estrogen were the same in both the control and treatment cycles. RU 486 caused a significant increase in uterine contractility expressed in Montevideo Units (MU) and a decrease in uterine tonus in comparison with corresponding data obtained in the control cycle. Following treatment with tamoxifen, uterine contractility was lower but the difference was not significant. PGF2 alpha invariably caused a stimulation of uterine contractility. However, treatment with the antihormones did not influence the response. The result of the present study indicates that the change in uterine contractility occurring in the latter part of the menstrual cycle and during menstruation is due to progesterone withdrawal.

Infertility: an approach to management in a district hospital in Ghana.

PIP: Up to 1/3 of women of child bearing age are infertile in certain African areas. Over 1000 patients registered at Bawku Hospital, Upper East Region, Ghana during an 18-month period, where a scheme for the investigation and treatment of infertile patients was established. The 5 main causes of infertility are: 1) tubal damage; 2) male factor; 3) anovulation; 4) uterine factor; and 5) unexplained. Special clinics are set up for infertility; outpatient staff are recruited. A preprinted questionnaire should be used for a uniform approach. The one used in Bawku is shown in the appendix. Health talks should be given. They should use the local language be at the right level, and use visual aids. In large clinics, numbers should be used to insure a 1st come, 1st served basis. A treatment protocol is important. When the patient 1st walks in, the infertility form is completed; appropriate investigations are done--hemoglobin, VDRL, seminal analysis, and cervical or high vagina swabs, and others--and the results are reviewed. The patient is encouraged to keep a menstrual calendar for 3 months. At the 2nd visit, the menstrual calendar is reviewed. A pelvic examination and a tubal patency test (TPT) are done. At the 3rd visit, abdominal and pelvic examinations are done and a TPT. Then patients can be diagnosed and counselled accordingly. At the last visit, further explanation is given, further TPTs are done if necessary, and anovulation is treated with clomiphene. The visits are spread out over 6 months. In unexplained fertility cases, the couple is told there is nothing wrong, they should keep trying. The idea that the man may be causing the infertility is foreign to many communities. This needs changing. 20% of infertility is due to male factor in Bawku. Male infertility is hard to cure. Cultural considerations prevent the clinician from telling the patient that her partner is infertile. They will tell her that there is nothing wrong with her. Approximately 15% become pregnant. The clinic has a strong psychological component.^ieng