Relationship Between TCM Syndrome Pattern and Immuno-endocrine Function in Patients with Infertility Induced by Chronic Pelvic Inflammation / 广州中医药大学学报

0.05) . Serum P level was much decreased in pattern 2 patients as compared with those in other pattern patients ( P0.05). [Conclusion] Serum P level is lower in the patients with CPI-induced infertility than that in the healthy, and varies in the patients with different patterns.

The regulation of the expression of membrane type-1 matrix metalloproteinase and gelatinase-A activation by progesterone in human osteoblast-like cells cultures / 中华老年医学杂志

Objective To characterize the effects of progesterone(P) on the expression of membrane type 1 matrix metalloproteinase (MT1 MMP) and gelatinase A activation in human osteoblast like cell strain MG 63 in order to understand the mechanism of progestin acting on the bone. Methods Semi quantitative RT PCR, Western blot, and confocal immunohistochemistry were used to study the actions of P on the expression of mRNA and protein of the MT1 MMP in cultured MG 63 cells. Zymogram of the gelatin and ELISA were performed to examine the effects of P on the activation of gelatinase A. Results Treatment with increasing dose of P in MG 63 cells caused a dose dependent increase in the expression of MT1 MMP mRNA ( P 0 05). Conclusions Our studies suggested that P might promote the bone formation by increasing MT1 MMP production in osteoblastic cells and thus played an important role in maintaining the osteogenic activity of osteoblasts and preparing the bone matrix for the subsequent bone cell migration and the deposition of new matrix.

Preregistration study on the safety and contraceptive efficacy of a progesterone-releasing vaginal ring in Chilean nursing women.

The contraceptive efficacy and safety of a progesterone-releasing vaginal ring (PVR) manufactured in Chile were compared to that of the Copper T 380A IUD (T-Cu) in nursing women enrolled at three Chilean clinics. A total of 285 volunteers chose to use the PVR and 262 the T-Cu. Plasma progesterone levels attained with the ring decreased from 25 to 14 nmol/L from month 1 to month 3 of use. Ring replacement was scheduled every 3 months. Volunteers continued in the study until weaning or completing the continuous use of four PVRs. No pregnancies occurred in 2320 and 2183 woman-months of exposure with the PVR and the T-Cu, respectively. Lower continuation rates in the first 6 months because of problems with use and a longer lactational amenorrhea were observed in the PVR than in the T-Cu group. Breast-feeding performance and infant growth were similar in both groups. These results confirm the high efficacy and safety of the PVR for nursing women and have led to the registration of the PVR by Chilean health authorities.

PIP: This study compares the contraceptive efficacy and safety of a progesterone-releasing vaginal ring (PVR) manufactured in Chile and a Copper T 380A IUD (T-Cu) in nursing women enrolled at three Chilean clinics. A total of 285 volunteers used the PVR and 262 used T-Cu. Plasma progesterone levels attained with the ring decreased from 25 to 14 nmol/l from month 1 to month 3 of use. Ring replacement was scheduled every 3 months. Volunteers continued in the study until weaning or completing the continuous use of 4 PVRs. There were no pregnancies in 2320 and 2183 woman-months of exposure with the PVR and the T-Cu, respectively. Lower continuation rates in the first 6 months because of problems with use and a longer lactational amenorrhea were seen in the PVR group. Breast-feeding performance and infant growth were similar in both groups. These results prove the high efficacy and safety of the PVR for nursing women. This has led to the registration of the PVR by Chilean health authorities.

Interleukin-6 and tumor necrosis factor-alpha concentrations in the intrauterine cavity of postmenopausal women using an intrauterine delivery system releasing progesterone. A possible mechanism of action of the intrauterine device.

Intrauterine devices (IUD) provide effective contraception. The current study evaluates the concentration of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in the intrauterine fluid of postmenopausal women using an intrauterine delivery system releasing progesterone (IDS-P). Intrauterine fluid was obtained by lavage, and IL-6 and TNF-alpha were analyzed using an enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed with a one-way analysis of variance (ANOVA). Intrauterine fluid IL-6 levels were 33.6 vs 6.09 pg/sample IDS-P vs no IDS-P (p = 0.0301). Intrauterine TNF-alpha levels for women using the IDS-P were higher than in nonusers, but the differences did not reach statistical significance. IL-6 and TNF-alpha levels were increased in the intrauterine cavity of postmenopausal women with an IDS-P. These data suggest that secreted cytokines could be a potential mechanism of IUD contraceptive efficacy.

PIP: This paper examines the possible mechanism of action of a progesterone-releasing IUD (P-IUD) by evaluating the concentration of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in the intrauterine fluid of postmenopausal women using such a device. IL-6 and TNF-alpha were examined using an enzyme-linked immunosorbent assay (ELISA), while the intrauterine fluid was obtained by lavage. Intrauterine fluid IL-6 levels were 33.6 vs. 6.09 pg/sample for P-IUD vs. non-P-IUD users (p = 0.0301). Higher intrauterine TNF-alpha levels were observed in women using the P-IUD than in nonusers. The cells found in the intrauterine fluid of the P-IUD users were mostly histiocytes (macrophages) based on their morphologic characteristics. Increased IL-6 and TNF-alpha levels were found in the intrauterine cavity of postmenopausal women using a P-IUD. These results indicate that cytokines could play a significant role in the contraceptive mechanism of action of the IUD when used by premenopausal women.

Review of newer contraceptive agents.

Advances in contraceptive technology have made birth control more effective, convenient, and safe. We review the newer products and some under development, including the latest oral contraceptives, injectable progesterone, subdermal progestin implants, progesterone-releasing IUDs, emergency contraception, and male contraception.

PIP: This paper reviews the latest developments in oral contraceptives (OCs), long-acting contraceptives such as injectable progesterone, subdermal progestin implants, progesterone-releasing IUDs, emergency contraception, and male contraception. Latest developments of OCs contain much lower doses of estradiol than the older preparations and uses newer progestins with less androgenic activity, thus causing fewer side effects. Depot-medroxyprogesterone acetate injections every 3 months prevent conception by suppressing the luteinizing hormone surge, thereby inhibiting ovulation. These contraceptive options are good for women in whom compliance may be low. Subdermal progestin implants have a failure rate of 0.8/100 woman-years for the first 5 years of use, increasing to 2/100 woman-years by the 6th year. They acts primarily by rendering the cervical mucus impenetrable to sperm. The progesterone-releasing IUDs, on the other hand, induce decidualization of the endometrium, thus inhibiting implantation. Among the postcoital contraceptives briefly discussed in this paper are the combined OCs (ethinyl estradiol and norgestrel), progestin-only compounds, the copper IUD, and mifepristone. The new developments of condoms, which are the mainstay of male contraception, include the new polyurethane condom, which is thinner, stronger, and less allergenic.

The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive.

BACKGROUND: Rifampin (INN, rifampicin), a CYP34A inducer, results in significant interactions when coadministered with combination oral contraceptives that contain norethindrone (INN, norethisterone) and ethinyl estradiol (INN, ethinylestradiol). Little is known about the effects of rifabutin, a related rifamycin. OBJECTIVES AND METHODS: The relative effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 microg ethinyl estradiol/1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. RESULTS: Rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] of ethinyl estradiol and the mean AUC(0-24) of norethindrone. Rifabutin significantly decreased the mean AUC(0-24) of ethinyl estradiol and the mean AUC(0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC(0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. CONCLUSION: In this study, rifampin (600 mg daily) was a more significant inducer of ethinyl estradiol and norethindrone clearance than rifabutin (300 mg daily), but neither agent reversed the suppression of ovulation caused by oral contraceptives. The carefully monitored oral contraceptive administration and the limited exposure to rifamycins may restrict the application of this study to clinical situations.

PIP: The relative effects of rifampin and rifabutin (a related rifamycin) on the pharmacokinetics and pharmacodynamics of ethinyl estradiol (EE) and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 mcg EE and 1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. Findings showed that rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC (0-24)] of EE and the mean AUC (0-24) of norethindrone. Rifabutin significantly decreased the mean AUC (0-24) of EE and the mean AUC (0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC (0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. This study suggests that rifampin (600 mg daily) was a more important inducer of EE and norethindrone clearance than rifabutin, but none of these agents were able to reverse the suppression of ovulation done by oral contraceptives.

Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): assessment of return of ovulation after three monthly injections in surgically sterile women.

The pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) on ovarian function were assessed through changes in serum progesterone concentrations. The data described here were obtained simultaneously with pharmacokinetic data presented in another article in this issue. Sixteen surgically sterile women with regular menstrual cycles were studied for one control cycle, three consecutive treatment months, and 3-5 months of follow-up. Suppression, followed by resumption of ovulation (the dynamic end point), was assessed by serum progesterone levels. Return of ovulation was presumptive based on progesterone concentrations > or = 4.7 ng/mL, as ultrasound was not used to determine the follicular/ovulatory status of these subjects. Luteal-like serum progesterone peaks were observed in all 16 women before drug administration, confirming the presence of ovulatory cycles. After the third monthly injection of MPA/E2C, progesterone concentrations were measured until demonstration of ovulation. Two women discontinued and three were lost to follow-up before this objective was achieved. Serum progesterone levels and, consequently, ovulation were suppressed beyond the entire dosing interval, indicated by the absence of any luteal-like progesterone peaks (serum progesterone concentrations did not exceed 1 ng/mL). The first normal ovulatory cycle, based on progesterone concentrations > or = 4.7 ng/mL, was observed in 11 women between days 63 and 112 after the third injection. Select medroxyprogesterone acetate parameters (i.e., area under the curve and minimum concentration) were correlated with return of ovulation. The correlation coefficients (r) were 0.757 and 0.492 for area under the curve and minimum concentration, respectively, indicating that return of ovulation is dependent, in part, on area under the curve and on the magnitude of the serum MPA trough level. In general, the higher the minimum concentration levels, the longer the time to return of ovulation. In conclusion, the return of ovulation, as confirmed by serum progesterone concentrations > or = 4.7 ng/mL, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E2C, suggesting that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.

PIP: This study assessed the pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C) (Lunelle monthly contraceptive injection) through changes in serum progesterone concentrations. A total of 16 surgically sterile women with regular menstrual cycles were studied for one control cycle, three consecutive treatment months, and 3-5 months of follow-up. Serum progesterone levels and, consequently, ovulation were suppressed beyond the entire dosing interval, indicated by the absence of any luteal-like progesterone peaks. The first normal ovulatory cycle, based on progesterone concentrations of 4.7 ng/ml or higher, was noted in 11 women between days 63 and 112 after the third injection. Select MPA parameters were correlated with return of ovulation. The correlation coefficients were 0.757 and 0.492 for area under the curve and minimum concentration, respectively, indicating that return of ovulation is dependent, in part, on area under the curve and on the magnitude of the serum MPA trough level. Generally, the higher the minimum concentration levels, the longer the time to return of ovulation. This study concluded that the return of ovulation, as confirmed by serum progesterone concentrations of 4.7 ng/ml or higher, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E2C. This indicates that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.

Lipid effects of an intrauterine levonorgestrel device or oral vs. vaginal natural progesterone in post-menopausal women treated with percutaneous estradiol.

BACKGROUND: The ideal progestin for combined hormone replacement therapy should be free of adverse effects on lipid metabolism. We therefore examined lipid profiles during continuous hormone replacement therapy (HRT) with an estradiol-gel combined with either a levonorgestrel-releasing intrauterine device (LNG-IUD) or oral/vaginal natural progesterone. METHODS: Sixty menopausal women recruited in this open, non-randomised parallel three-group study received percutaneous gel containing 1.5 mg of estradiol daily. Progestin was administered to the women with an LNG-IUD (n = 20), as oral natural progesterone (n = 21) 100 mg daily on the 1-25 calendar days of the month or as vaginal progesterone (n = 19) 100-200 mg daily on the 1-25 calendar days of the month. Serum concentrations for total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and sex hormone binding globulin (SHBG) were measured at 0, 6 and 12 months. The median (and 95% confidence interval) of the serum SHBG, total, LDL-, HDL- cholesterol and triglycerides concentrations at baseline and after 6 and 12 months of the study and the ratio of 6 and 12 months values to baseline values were calculated. RESULTS: Total cholesterol was significantly decreased (8%) in the vaginal progesterone group at the end of the trial. HDL-cholesterol did not change in either of the progesterone groups, while a slight but transient decrease (median 15%) was seen at 6 months in the LNG-IUD group. There were no significant changes in triglycerides or LDL-cholesterol concentrations in any group. SHBG did not change significantly in the LNG-IUD and vaginal progesterone groups, while a slight but transient increase was seen in oral P group at 6 months. CONCLUSIONS: As the only significant harmful effect observed was a transient decrease in HDL-cholesterol in the LNG-IUD group at 6 months, each of these HRT-administration methods can be regarded as being safe in their effects on lipid metabolism.

PIP: This study examined the lipid profiles during continuous hormone replacement therapy (HRT) with an estradiol gel combined with either the levonorgestrel-releasing IUD (LNG-IUD) or oral/vaginal natural progesterone. In an open and nonrandomized parallel three-group study conducted in Finland, 60 menopausal women were administered a percutaneous gel containing 1.5 mg of estradiol daily. Progestin was administered to 20 women with an LNG-IUD, as oral natural progesterone (100 mg daily) to 21 women on calendar days 1-25, or as vaginal progesterone (100-200 mg daily) to 19 women on calendar days 1-25. Serum concentrations of total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, and sex hormone binding globulin (SHBG) were measured at 0, 6, and 12 months. Results revealed an 8% decrease of total cholesterol in the vaginal progesterone group. HDL-cholesterol remained stable in both progesterone groups, with a 15% decrease at 6 months in the LNG-IUD group. Triglycerides and LDL-cholesterol concentrations were found to have insignificant changes. SHBG was observed to be stable in the LNG-IUD and vaginal progesterone groups, with a slight increase seen in the oral progesterone group after 6 months. This study confirms the safety of this type of HRT with regard to lipid metabolism, except for the transient decrease in HDL-cholesterol among LNG-IUD users at 6 months.

Endometrial morphology during hormone replacement therapy with estradiol gel combined to levonorgestrel-releasing intrauterine device or natural progesterone.

OBJECTIVES: To evaluate endometrial responses to three different forms of amenorrhea-inducing HRT in postmenopausal women. MATERIAL AND METHODS: Fifty-one postmenopausal women completing a one-year HRT trial with percutaneous estradiol gel containing 1.5 mg estradiol daily combined with a levonorgestrel-releasing intrauterine device (LNG-IUD) (n=18), or natural progesterone 100 mg daily orally (n= 19) or vaginally (n=15) during 1-25 calendar days of each month. Endometrial thickness and uterine size were measured by transvaginal ultrasound, and endometrial cytology/histology was assessed from specimens taken by needle aspiration before the study and at 12 months. RESULTS: Before medication, the median endometrial thickness was 2.0 mm in the LNG-IUD group, 2.4 mm in the oral P group and 2.5 mm in the vaginal P group. At 12 months of therapy the respective values, 3.0, 2.7 and 2.4 mm, did not differ significantly from the initial values. LNG-IUD induced epithelial atrophy in all women, which was accompanied by stromal decidualization in 12 women. On the contrary, only four women in the oral P group and five women in the vaginal P group had an inactive or atrophic endometrium. The remaining cases were dominated by proliferative features. No hyperplasia was seen in any of the groups. CONCLUSION: LNG-IUD appeared to be an effective method of counteracting the stimulatory effect of estrogen on the endometrium, whereas natural progesterone given orally or vaginally was not sufficiently effective in this function at the doses used. The vaginal and oral administrations of progesterone did not differ from each other in this respect.

PIP: This study evaluated the endometrial morphological response to the levonorgestrel-releasing IUD (LNG-IUD) and to natural progesterone administered orally or vaginally in postmenopausal women using percutaneous estradiol gel on a daily basis. The study employed 51 postmenopausal women who completed a 1-year hormone replacement therapy trial of 1.5 mg estradiol daily combined with a LNG-IUD (n = 18), 100 mg oral progesterone (n = 19), or 100 mg vaginal progesterone (n = 15) during 1-2 calendar days of each month. Using a transvaginal ultrasound, endometrial thickness was measured prior to and 12 months after the study. Prior to the study, endometrial thickness was 2.0, 2.4, and 2.5 mm for the LNG-IUD, oral progesterone, and vaginal progesterone groups, respectively. During the transvaginal ultrasound (after 12 months) the respective values were 3.0, 2.7, and 2.4 mm, respectively, which was considered normal among postmenopausal women. 12 of the women who were administered the LNG-IUD were found to have epithelial atrophy accompanied by stromal decidualization. On the other hand, 4 women in the oral progesterone and 14 in the vaginal progesterone groups were found to have inactive or atrophic endometrium. Proliferative features dominated the remaining cases, while hyperplasia was not observed in any of the cases. This study confirms the efficacy of the LNG-IUD in suppressing the stimulatory effect of estrogen on the endometrium, while oral and vaginal progesterone were not sufficiently effective at the doses used.

The effects of progesterone and progestins on endometrial proliferation.

A total of 99 premenopausal and 27 postmenopausal women were evaluated to determine the quantity of glandular proliferation resulting from progestin inhibition of estrogen-primed subjects and of subjects without hormonal stimulation. Endometrial glandular proliferation rates were determined by using mitosis counts, proliferating-cell nuclear antigen (PCNA), and nuclear cyclin (MIB1) immunocytological staining. The endometria of normally cycling premenopausal women, of women who received a synthetic progestin, and of untreated postmenopausal women were studied. In untreated normally cycling premenopausal women, the proliferation of the glandular epithelium was increased during the follicular phase and decreased during the luteal phase. Premenopausal women receiving a synthetic progestin and untreated postmenopausal women who were not estrogen-primed showed minimal epithelial proliferation. Endometrial glandular proliferation is inhibited by endogenous progesterone in premenopausal women. Endometrial proliferation is markedly reduced in premenopausal women receiving a synthetic progestin and in untreated postmenopausal women.

PIP: Use of micronized progesterone or a synthetic progestin has been shown to counter the proliferative effect of estrogen on the endometrium in pre- and postmenopausal women. The present study measured endometrial glandular proliferation rates in 99 pre- and 27 postmenopausal US women. Determinations were based on mitosis counts and both proliferating cell nuclear antigen and nuclear cyclin immunocytologic staining of endometrial tissue. In the untreated, normally cycling premenopausal subjects, glandular epithelial proliferation increased during the follicular phase and decreased during the luteal phase. Premenopausal women who received a synthetic progestin and untreated postmenopausal women who were not estrogen-primed showed minimal epithelial proliferation. The mean mitosis rate of proliferative phase glands was 12.3 compared with 1.6 and 0.01 after administration of the oral contraceptives norethindrone or norethynodrel, respectively. Among premenopausal women, the intensity of the stromal pseudodecidualization and inhibition of glandular development was greatest in those receiving monthly medroxyprogesterone acetate injections. The combination of progestin potency, dosage, and duration determined the mitoses, stroma, and glands that were present in the three groups of subjects. The methods used in this study may be of use in determining optimal dosages of exogenous progestins in women who are receiving hormone replacement therapy and the potential exists for predicting adverse endometrial responses to progestational therapy.

Effects of oral contraceptives containing different progestogens on sodium-lithium countertransport in normal females.

In view of the lack of unanimity on the effect of long-term intake of combined oral contraceptives (OC) on external sodium-dependent lithium efflux, otherwise known as sodium-lithium countertransport (SLC), we undertook a double-blind study to investigate the possible interaction between SLC and OC in healthy women with regular menstrual cycles. In a group of 17 volunteers, aged 27.0 +/- 1.1 years (mean +/- s.e.m.) and weighing 61.4 +/- 2.0 kg, ingestion of 30 microg ethinyloestradiol + 150 microg desogestrel for 3 months caused an increase in SLC activity from a baseline value of 0.254 +/- 0.017 mmol/lcell x h to 0.274 +/- 0.017 mmol/lcell x h (P = 0.05). The activity of the transport system after 6 months treatment remained higher than at baseline (0.280 +/- 0.016 mmol/lcell x h, P < 0.025) but was comparable to that at 3 months. Blood pressure and weight remained unaltered during the study period. In a comparable group of 16 volunteers of age 26.1 +/- 1.3 years and weight 63.5 +/- 2.1 kg, control SLC activity (0.218 +/- 0.012 mmol/lcell x h) was comparable to that after 3 months (0.215 +/- 0.011 mmol/lcell x h) and 6 months (0.216 +/- 0.011 mmol/lcell x h) intake of 35 microg ethinyloestradiol + 2 mg cyproterone acetate. Body weight and blood pressure remained similarly unchanged. These results not only confirm that long-term intake of OC may cause increased SLC activity, but also suggest that the type of the progesterone in the medication used could be an important determinant of such interaction.

PIP: This double-blind study investigates the possible interaction between sodium-lithium countertransport (SLC) and oral contraceptives (OCs) in healthy women with regular menstrual cycles. 33 healthy females with regular menstrual cycles aged 18-35 years and weighing 43.5-73.0 kg were recruited. Each volunteer was randomly given either a 30 mcg ethinyl estradiol/150 mcg desogestrel combination or a 35 mcg ethinyl estradiol/2 mg cyproterone acetate combination. For each volunteer, blood was taken in the morning of days 15-18 of their menstrual cycle for biochemistry and SLC assay before treatment, and at the same stage of the cycle after 3 and 6 months. The study showed different effects of two different OC preparations in two groups of otherwise comparable volunteers. Administration of ethinyl estradiol/cyproterone acetate combinations for 6 months was not associated with alteration in any of the parameters measured. However, SLC activity increased after 3 and 6 months of ethinyl estradiol/desogestrel medication. These results not only confirm that long-term intake of OCs may cause increased SLC activity, but also suggest that the type of progesterone in the medication used could be an important determinant of such alteration in the activity of the transport system.

[Late effects of sterilization in women]. / Naisen sterilisaation myöhäisvaikutukset.

Sterilization affects measurably the circulation and the functioning of the ovaries, but further studies are required to estimate the clinical meaning of the change.

PIP: In Finland, every year a total of 11,000 female sterilizations are carried out, whereas worldwide 400 million such procedures are expected to be performed by the year 2000. In the past decade, major changes have occurred in the technical aspects of the procedure. Unilateral and bilateral endocoagulation of the Fallopian tube used to be standard procedure, but at the present time, when using the method of choice, laparoscopy, a clip ties the tube. Post-sterilization symptoms include pain (10-26% of cases), pain irrespective of menstrual cycle (6-40%), dyspareunia (4%), premenstrual tension (6-40%), and prolonged menstruation. Arterial blood flow between the uterus and Fallopian tube may be disturbed and tissue damage may result infrequently. Earlier methods of female sterilization produced more tissue damage, as clips affect blood circulation. In one study, lower abdominal circulation was measured by Doppler ultrasound and compared with nonsterilized subjects 2 days before sterilization, 2 days after, and 3 months later. The results indicated that patients whose uterine blood flow had decreased subsequently returned to the previous normal value, but in the ovaries the change was greater and return to the previous value did not occur. The author's own study used salivary samples 1 month before sterilization, 3 months after sterilization, and 1 year afterwards during a whole menstrual cycle. Total progesterone values slowly decreased 1 year after sterilization. Within the menstrual cycle, the peak of the progesterone level was the lowest 3 months after sterilization and it did not reach the pre-sterilization level. Sterilization exerts a measurable effect on the ovaries, but more investigations are needed to confirm this finding.

[The importance of subsequent contraception in reducing unwanted pregnancies]. / Jälkiehkäisyllä tärkeä sija ei-toivottujen raskauksien vähentämisessä.

The most established hormonal method of subsequent contraception is the so-called Yuzpe-method; another important method is placement of a copper coil. Hormonal subsequent contraception has no health-hazardous side effects, so there is nothing to prevent its use but a known pregnancy. More information about subsequent contraception and easier distribution are seen as important means of decreasing unwanted pregnancies as well as abortions.

PIP: Postcoital contraceptives have been known for 3 decades. In recent years the combination estrogen/levonorgestrel has been popular. It is administered 72 hours after intercourse and repeated 12 hours later. The use of the IUD within 5 days of coitus is another option. In Finland, the 4-tablet method was introduced in the mid-1980s. In 1996, a total of 32,000 such packets were sold. Women under the age of 25 used them primarily. A 1994 study demonstrated that the 18-24 age group used it at least once, versus 1-3% for those over 30 years of age. A 1996 study revealed that secondary school students were quite familiar with this method. Since hormonal contraceptives are not 100% reliable, up to 2% of users still get pregnant. 3-4% get pregnant if the coitus occurred in the middle of the cycle. If someone still gets pregnant, the fetus is not exposed to any harm by using them. Nausea and headache occur in half of the women who use them and vomiting in 15-20%. It is recommended that a pregnancy test be performed 2-3 weeks after the use of postcoital methods. The approach of using both OCs and the condom is increasingly accepted among young people. Counseling is indispensable for adolescents in order to avoid resorting to abortion, which should never be a method of family planning. There are calls for dispensing postcoital methods over the counter and allowing nurse-midwives to dispense them. The number of abortions in Finland dropped significantly during the 1990s, a result that can be partly credited to postcoital methods.

WHO scientific group meeting on cardiovascular disease and steroid hormone contraceptives.

PIP: More than 100 million women worldwide are thought to use steroid hormone contraceptive methods, with an estimated 93 million women using combined oral contraceptives (COCs). The composition and use of these contraceptive preparations, especially those of COCs, have changed dramatically over the years. The World Health Organization (WHO) convened a Scientific Group Meeting on Cardiovascular Disease and Steroid Hormone Contraception during November 3-7, 1997, to review current scientific data on the use of steroid hormone contraception as they relate to the risk of myocardial infarction, ischemic and hemorrhagic stroke, and venous thromboembolic disease. The group also reviewed the incidence of cardiovascular disease among women of reproductive age in general, how the effect of risk factors for cardiovascular disease may be changed using hormonal contraceptives, and whether different compositions of COCs have different cardiovascular risk profiles. The group was comprised of the authors of background papers prepared for the meeting and experts from around the world. The scientific group's conclusions are presented. The incidence and mortality rates of all cardiovascular diseases are very low among reproductive-age women. For women who do not smoke, who have their blood pressure checked, and who do not have hypertension or diabetes, the risk of myocardial infarction in COC users is not increased regardless of age. While current users of COCs have a low absolute risk of venous thromboembolism, their risk is still 3-6 times greater than that of nonusers, with the risk probably being highest during the first year of use.^ieng

Cyclic and individualized administration of gonadotropin-releasing hormone agonists plus progestogens: an alternative protocol for contraception.

Twenty-one women presenting with different diseases, with absolute or relative contraindications to hormonal contraception or the use of intrauterine devices, received 300-600 micrograms/day buserelin intranasally from the 1st to the 21st day, and 5 mg/day norethisterone acetate orally from the 16th to the 23rd day of the cycle for a total of 245 cycles. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol and testosterone were determined on days 3-5 and 13-15 of the cycle, while progesterone determinations and ovarian sonography were performed during the second half of the cycle. According to progesterone values, 92.7% of the treatment cycles were anovulatory, while in one cycle pregnancy was detected (0.4%). Values of serum LH, FSH and estradiol were low, and in most of the cycles ovarian follicular development was limited to follicles < or = 11 mm. In 21 treatment cycles (9%), statistically significant increases in FSH (p < 0.0001) and LH (p < 0.02), as well as ovarian proliferation to preovulatory follicles or luteinized follicles, were found. It appears that in spite of the high cost of medication and monitoring of patients, this regimen could be useful as an alternative in cases where other forms of contraception are contraindicated or have failed.

Transdermal estrogen with a levonorgestrel-releasing intrauterine device for climacteric complaints versus estradiol-releasing vaginal ring with a vaginal progesterone suppository: clinical and endometrial responses.

OBJECTIVE: Our purpose was to compare the effects of a new estradiol-releasing vaginal ring with progesterone given as a vaginal suppository, versus the efficacy, safety and acceptability of an intrauterine device releasing levonorgestrel combined with estradiol, delivered transdermally from a patch. Climacteric symptoms, bleeding pattern and endometrial histologic features were studied. METHODS: Fifty six parous, postmenopausal women with urogenital symptoms were allocated in two groups for one year: 28 women receiving estradiol by a vaginal ring and a 100 mg vaginal progesterone suppository 7 days every month and 28 women receiving a continuous transdermal daily dose of 50 micrograms of estradiol with a levonorgestrel-releasing intrauterine device inserted. All the patients were subjected to vaginosonographic examination followed by thorough pathological examination of the uterine curetting samples. RESULTS: A mean endometrial thickness (double layer) of 2.9 and 3.0 mm, respectively, was found to be predictive of normal endometrium. Both treatment regiments effectively relieved climacteric symptoms. Endometrial proliferation was not observed. Spotting was more common in the intrauterine device group than in the vaginal ring group. CONCLUSIONS: Treatment of urogenital symptoms in postmenopausal women with these two forms of hormone replacement therapy is shown to be an effective and safe method, exhibiting advantages over other methods of treatment.

[Contraceptive agents and risk of thrombosis]. / Antikonzeptiva und Thromboserisiko.

In the late sixties and seventies, publications of the Royal College of General Practitioners in England reported that in women using oral contraceptiva the incidence of venous thromboembolism is increased by two to four fold. Moreover, it was demonstrated, that these alterations in coagulation were induced by ethinylestradiol in a dose dependent manner. Following these findings, its dosage was lowered from more than 100 micrograms to 20-30 micrograms per day. More recently, the role of gestagens in inducing thrombosis has also been debated. Different authors observed an increased risk for venous thromboembolism in women using third generation pills containing gestoden or desogestrel compared with users of second generation levonorgestrel contraceptiva. These reports have generated a lot of concern and fear in the patients as well as doctors and have led to a drastic fall in the use of oral contraceptives. Due to the unavailability of safe contraceptive alternatives, the number of women experiencing unwanted pregnancy and its complications increased significantly. Indeed, direct proof for the role of gestagens in inducing thromboembolism is still lacking as the protocol designs of these studies do not allow us to infer whether the effects are due to the gestagens or to confounding variables. Hence, the discussions were beneficial for clinicians to remember the importance of checking the patient for individual and family risks for thrombosis before handling out a pill prescription.

PIP: The pathophysiological basis of blood coagulation includes hemostatic causes and thrombophilia (protein C deficiency, protein S deficiency, APC resistance, plasminogen deficiency, antithrombin III deficiency, hyperhomocystinemia, lupus anticoagulans and anticardiolipin antibodies). The effect of female sexual steroids on coagulation has been observed: ethinyl estradiol produced an increased risk of thromboembolism. Also, there was a pronounced increase of fibrin division products among users of higher EE doses. The effect of gestagens on coagulation was found to be contradictory. The risk of thrombosis as related to oral contraceptives (OCs) was investigated in several studies. Desogestrel and gestoden-containing OCs produced a higher incidence of thrombosis than levonorgestrel-containing pills. A WHO multinational case-control study was carried out in 21 centers and 17 countries during 1989-93, including a total of 1143 cases and 2998 controls. The risk of thrombosis was 2-3 times higher among women using gestoden or desogestrel-containing OCs than those using LNG-containing OCs. Similarly, there was a 1.58 increased risk according to a case-control study using data from England and Germany. A 1995 study of 700 medical practices in Great Britain involving 238,130 women showed increased risk for gestoden (1.8) and desogestrel (1.9). Another 1995 study used the data of 697,000 women from 398 practices in England and registered 116 cases of thromboembolism. There was a risk three times higher for all ovulation inhibitors among cases compared to controls, as well as a pregnancy risk 5.9 times higher. Nonetheless, no definitive conclusion can be drawn from all of these epidemiological studies, which could challenge the prevailing view on contraceptive behavior.

Role of oral contraceptives in the growth of a multilobular adenoma associated with a hepatocellular carcinoma in a young woman.

BACKGROUND: The occurrence of hepatocellular neoplasms is frequently reported in young females. The role of oral contraceptives in the development of these tumors is considered. METHODS: A 14-cm tumor was diagnosed in a 24-year-old female who had been taking the contraceptive pill for the last 3 years. Numerous blocks of this lesion were histologically and immunohistochemically analyzed. Some fragments of the lesion were snap-frozen in order to search for sex hormonal receptors and hepatitis B and C virus. RESULTS: On histological examination, the tumor was found to be a hepatocellular, multilobular adenoma with small foci of hepatocellular carcinoma. Neither hepatitis B virus nor hepatitis C virus was found in serum or in the tumor. Nuclear estrogen receptors and progesterone receptors were detected by immunohistochemical analysis in both the adenoma and the carcinoma, but only progesterone receptors were detected by a radio-ligand binding assay in the tumor. CONCLUSION: This finding suggests that the contraceptive pill may stimulate the growth of hepatocellular, multilobular adenomas through the binding of hormonal compounds to their specific receptors within tumoral cells.

Expression of progesterone receptor mRNA in the endometrium during the normal menstrual cycle and in Norplant users.

The expression of endometrial progesterone receptor mRNA during the human menstrual cycle and in Norplant users was studied using digoxigenin-labelled ribonucleic probes for in-situ hybridization on 6 microns paraffin embedded endometrial sections. The staining intensity was scored blind semi-quantitatively. Blood ovarian steroid concentrations were measured in Norplant users. All data were analysed by analysis of variance. Glandular progesterone receptor mRNA concentrations were low during the menstrual-to-early proliferative stage but increased during the early-to-mid to late-proliferative stage then declined non-significantly over the secretory stage. No such variation was observed in stromal cells. Progesterone receptor mRNA concentrations were lower in Norplant than controls during early-to-mid to late-proliferative stages (in glandular epithelium and stroma) and during secretory stage (in stroma only). Norplant subjects with amenorrhoea had higher concentrations of stromal progesterone receptor mRNA but lower plasma oestrogen concentrations than subjects with breakthrough bleeding. The pattern of variation in progesterone receptor mRNA concentrations during the normal menstrual cycle resembles the published pattern for the receptor protein. The results demonstrate: (i) a differential sensitivity of glandular and stromal progesterone receptors to steroid regulation; (ii) in contrast to previous findings of an increase in immunoreactive progesterone receptor protein in Norplant endometrium, progesterone receptor mRNA concentrations in these tissues were reduced; and (iii) there was significantly more progesterone receptor mRNA in subjects with amenorrhoea than in those with breakthrough bleeding.

PIP: At Monash Medical Center in Victoria, Australia, and at the University of Indonesia in Jakarta, researchers used digoxigenin-labeled ribonucleic probes for in-situ hybridization in the endometrium of 53 women across the normal menstrual cycle (controls) and of 39 Norplant users (cases), respectively, to examine the expression of progesterone receptor mRNA in the endometrium during the normal menstrual cycle and in Norplant users. They detected progesterone receptor mRNA in the glandular epithelium and stromal cells at all stages of the menstrual cycle. Concentrations of progesterone receptor mRNA staining in the glands increased from stage 1 (the menstrual to early proliferative stage), when there was little progesterone receptor mRNA staining, to stage 2 (early-to-mid proliferative to late proliferative stage) (1.35 vs. 2.25 staining intensity score; p 0.01). Thereafter, they fell steadily, but not significantly so. On the other hand, concentrations of progesterone receptor mRNA staining in the stroma did not vary during the menstrual cycle. Most endometria of Norplant users had detectable progesterone receptor mRNA in both the glandular epithelia and stromal cells. The endometria of Norplant users had less progesterone receptor mRNA staining in glandular epithelia than stage 2 of the cycle of the controls (1.5 vs. 2.25 score; p 0.01). The Norplant stroma also had less progesterone receptor mRNA than stages 2 (1.75 vs. 2.5 score; p 0.05) and 3 (1.75 vs. 2.5 score; p 0.01). Among Norplant users, the amenorrhea group had more progesterone receptor mRNA staining in the stroma than the bleeding group (2.5 vs. 1.75 score; p 0.05). It had lower plasma concentrations of estrogen than the bleeding group (200.8 vs. 523.9 pmol/l; p 0.05). There were no differences in the plasma progesterone concentrations, however. These findings confirm that there is a significant relationship between reduced endogenous estrogen concentrations and reduced breakthrough bleeding in users of progestin-only contraceptives. They show that glandular and stromal progesterone receptors have different sensitivity to steroid regulation.

Ultrasonographic and endocrine evaluation of ovarian function among Norplant implants users with regular menses.

With the objective of evaluating the ovulatory function among long-term Norplant implants users with regular menstrual cycles, we undertook this prospective study including 11 Norplant implants users and 11 control women who were not using hormonal methods of fertility control. Exposed and unexposed women had had at least three regular menstrual cycles preceding enrollment. All women were followed during one menstrual cycle by serial vaginal ultrasound and estradiol (E2), progesterone (P), LH, and FSH measurements. Three Norplant implants users ovulated, three had luteinization of an unruptured follicle (LUF), three had persistent follicle growth up to a mean of 33 mm without rupture, and two had no follicular development beyond 16 mm. Ten of the controls had normal ovulation and one had LUF. Mean peak LH and FSH among Norplant implants users who ovulated were three- to four-fold lower than among controls. Although users of Norplant implants with regular cycles frequently have luteal activity, the results of this study suggest that elevation of P during the second half of the cycle does not necessarily indicate ovulation has occurred and may frequently be associated with the presence of luteinized unruptured follicle. When ovulation occurs, there are usually abnormal hormone levels (low LH/FSH peak, low progesterone) which may also contribute to the contraceptive effect of Norplant implants.