The pattern of estradiol and progesterone differs in serum and tissue of benign and malignant ovarian tumors.

Epidemiological studies have indicated a relationship between gonadal steroid hormones and ovarian cancer. A production of both estradiol and progesterone by ovarian cancers has been demonstrated. The local steroid concentrations and the putative relation to histopathological and clinical condition were investigated herein. Ovarian tissue, ovarian tumor cyst fluid, ovarian vein samples and peripheral serum concentrations of estradiol and progesterone in pre- and post-menopausal women, subdivided into groups with normal ovaries, benign, borderline and malignant ovarian tumors, were quantitatively assessed. Both ovarian tissue concentrations of estradiol and progesterone were more than 100-fold higher than in serum. Based on differences in concentrations between different ovarian tumor groups, the data is not coherent with the previously suggested increased production of estradiol and progesterone in ovarian cancer tissue, since post-menopausal women with ovarian cancer presented lower median tissue hormone levels, most pronounced between malignant and benign tumors; median (25 and 75 percentile) estradiol; 9.40 (6.67-15.50) vs 16.44 (12.49-23.20), p=0.02 and progesterone; 308 (240-575) vs 957 (553-1143) pmol/g wet weight, p<0.01, n=81. Lower concentrations of estradiol, but not progesterone, were found in ovarian cancer tissue, ovarian cyst fluid and peripheral serum in patients with FIGO stages 3 and 4 than in stages 1 and 2. The novel finding of a large ovarian tissue to serum difference of both estradiol and progesterone indicates an important role of ovarian tissue concentrations in tumor biology and raises the question of adequate doses of anti-hormonal therapy in women with ovarian cancer.

Clinical and pregnancy outcome following ectopic pregnancy; a prospective study comparing expectancy, surgery and systemic methotrexate treatment.

BACKGROUND: The improved possibility of an early diagnosis of ectopic pregnancy by use of serial quantitative beta-subunit human chorionic gonadotropin hormone levels together with transvaginal ultrasound has opened up options for conservative treatment. Systemic methotrexate treatment of unruptured ectopic pregnancy has emerged as a safe and effective alternative to surgical procedures. The aim of the present study was to investigate the effectiveness of methotrexate treatment in routine clinical practice, but also to assess pregnancy outcome during a 2.5-year follow-up period. METHODS: All patients presenting to the Department of Obstetrics and Gynecology, Umeå University Hospital, with signs and symptoms of ectopic pregnancy between January 1, 1995 and December 31, 1997 were included in this prospective study. Patients with ectopic pregnancy were either managed expectantly, treated with methotrexate or by laparoscopic or open surgery (salpingostomy/salpingectomy). Systemic methotrexate (Pharmacia & Upjohn, Stockholm, Sweden) was administered as an intramuscular injection of 50 mg/m(2). RESULTS: One hundred and seven patients presented with signs and symptoms of a possible ectopic pregnancy, of these 89 patients eventually were diagnosed as having an ectopic pregnancy. Twenty-six (29%) patients were treated with methotrexate, 46 (52%) patients with laparoscopy or laparotomy, and 17 (19%) patients by expectant management. Success rate in the methotrexate group, after one or more injections, was 77% (20 patients out of 26). The mean time to resolution was 24+/-9 days. There was no difference in pregnancy rate following methotrexate treatment compared to surgical treatment. CONCLUSIONS: Systemic single-dose methotrexate treatment is a safe treatment option with a reasonably high success rate, with similar probability of a later intrauterine pregnancy as conventional surgical treatment.

A randomized, double-blind, multicentre study comparing the clinical effects of two sequential estradiol-progestin combinations containing either desogestrel or norethisterone acetate in climacteric women with estrogen deficiency symptoms.

OBJECTIVES: The aim of this study was to compare a new estradiol-desogestrel (E2-DG) regimen with an E2-norethisterone acetate (NETA) combination (Trisekvens) regarding the treatment of menopausal complaints, bleeding pattern, histology of the endometrium and the occurrence of adverse experiences. METHODS: A total of 310 peri-/postmenopausal women with climacteric symptoms were randomly allocated to oral sequential treatment with either the E2-DG combination (1.5 mg E2 for 24 days with 0.15 mg DG for the last 12 days followed by 1 placebo tablet for 4 days) or with the E2-NETA combination (Trisekvens, 2 mg E2 for 22 days with 1 mg NETA for the last 10 days followed by 1 mg E2 for 6 days). Treatments were administered double-blind for 12 cycles of 28 days. RESULTS: One hundred and four women, 48 in the E2-DG group and 56 in the E2-NETA group, discontinued the study due to bleeding irregularities and various adverse effects. Both treatments reduced menopausal symptoms and complaints effectively and almost equally. The alleviation of perspirations and the improvement of general fitness were more apparent (P = 0.009) during cycle 1 with the E2-NETA treatment but were greater (P < 0.02) during the last 9/10-12 cycles of E2-DG treatment compared to E2-NETA. Regular withdrawal bleeding appeared in 93% and 90% of the women during treatment with E2-DG and E2-NETA, respectively. Intermenstrual bleeding occurred in 8% of women receiving E2-DG and in 13% of women treated with E2-NETA. The corresponding figures for intermenstrual bleeding-spotting were 21% and 22%. Secretory endometrium was detected in 65% and 54% of the samples taken at the end of treatment with E2-DG and E2-NETA, respectively. No hyperplasia or atypia was found. No serious adverse events related to treatment occurred. CONCLUSIONS: Both regimens alleviated effectively menopausal complaints and did not induce hyperplasia of endometrium. The minor differences recorded between the two regimens were probably due to the differences in their composition concerning the amount of estradiol and its distribution along the cycle, the amount and type of progestin and the length of estradiol/progestin combination phase.

On the value of placental alkaline phosphatase as a marker for gynecological malignancy.

A sensitive catalytic assay for placental alkaline phosphatase (PLAP) was used to quantify enzyme levels in sera from women with malignant gynecological tumors, i.e. cervical carcinoma, ovarian carcinoma and carcinoma of the breast. Values were compared with those of a reference group of 155 healthy individuals. In this group, basic mean levels of the enzyme amounted to 0.06 +/- 0.08 mumoles X min-1 X 1(-1) (mean +/- SD), which corresponds to 0.3 +/- 0.4 ng/ml (mean +/- SD) purified placental alkaline phosphatase. Enzyme levels were not significantly affected by age, whereas sex gave slightly higher values for women in all age groups. This difference was statistically significant (p less than 0.001). The discriminating capacity of PLAP as a tumor marker was analysed with this assay and compared in sensitivity with a radio-immunoassay. A cut-off level of 0.2 mumoles X min-1 X 1(-1), corresponding to 1 ng/ml enzyme protein as measured by the radio-immunoassay, detected 23-68% of the tumor patients, giving false-positive results from the control group in the order of 5%. Corresponding values at a cut-off level of 0.3 mumoles X min-1 X 1(-1) (1.5 ng/ml) gave values 20-44% and 2%, respectively. The present investigation emphasizes that sensitivity in assays of placental alkaline phosphatase, whether catalytic or immunological, must not exceed ng-level.

Specific binding of 17 beta-estradiol in the human thymus.

Many observations suggest that estrogenic preparations can depress cell-mediated immune reactions. Since cell-mediated immunity is thymus-dependent, the estrogen-binding properties of human and mouse thymus tissue were studied with the use of an aqueous two-phase separation system. A high-affinity and low-capacity estrogen binding was found in human thymus tissue from six prepubertal children of both sexes and two grown women. A similar specific binding was found in the mouse thymus and in the human uterus. The association constant (Ka) for the binding in the human thymus was 16.01 +/- 8.98 X 10(9)M-1. The human uterus, which is known to possess estrogen receptors, had Ka values in the same range. The binding seems to be located in the reticuloepithelial cells of the thymus. Data suggest that the human thymus is a target organ for estrogens, which may influence lymphocyte function during therapy.

Percutaneous oestrogen therapy opposed by lynestrenol or natural progesterone--effects on circulating oestrogens, FSH, sex hormone binding globulin and pregnancy zone protein.

Three groups of post-menopausal women were treated with percutaneous 17 beta-oestradiol 3 mg daily opposed by lynestrenol 5 mg or natural micronized progesterone 200 mg and 300 mg, respectively. During 6 mth of cyclic replacement oestrogen serum levels were increased corresponding to follicular phase values. The pre-treatment ratio E1/E2 was unchanged which is in contrast to oral therapy. Progesterone had a much weaker effect on FSH levels than lynestrenol. Women treated with progestogen had regular withdrawal bleedings, while the micronized progesterone was insufficient in this respect. No increase of the oestrogen-sensitive liver proteins, sex hormone binding globulin (SHBG) and pregnancy zone protein (PZP), was recorded in spite of a marked increase in circulating oestrogens.

Free testosterone levels during danazol therapy.

Danazol is a testosterone (T) derivative widely used in the clinical treatment of endometriosis. Its mechanism of action is poorly understood, but is side effects are mainly androgenic. Previously it was demonstrated that danazol can displace T from sex-hormone-binding globulin (SHBG). The binding properties of danazol to SHBG and albumin were studied with the use of labeled danazol in an aqueous two-phase equilibrium partition system. Levels of total T, SHBG, and albumin were measured in 16 women undergoing danazol treatment for endometriosis. Thereafter, free and protein-bound T levels were calculated. A marked rise in free T was found during danazol therapy as compared with pretreatment levels. The data suggest that many of the effects of danazol could be explained by increased levels of free T during treatment.

A comparison of liver protein induction in postmenopausal women during oral and percutaneous oestrogen replacement therapy.

Two groups of postmenopausal women with climacteric symptoms were investigated during unopposed cyclic replacement therapy with tablets of micronized 17 beta-oestradiol (2 mg daily) and percutaneous 17 beta-oestradiol (3 mg daily). The resultant serum levels of 17 beta-oestradiol, total oestrone and three liver proteins: sex-hormone-binding globulin (SHBG), pregnancy-zone protein (PZP) and caeruloplasmin were followed. In both groups similar levels of serum 17 beta-oestradiol (ca 500 pM) were recorded, while the increase of total oestrone was much more pronounced after oral treatment. During oral therapy the serum levels of all three proteins showed a marked increase after the first cycle and the levels then remained stable. In contrast, protein levels were unchanged during percutaneous treatment, in spite of the highly increased concentrations of circulating oestrogens. This observation is important as several side-effects of oestrogen therapy may be related to liver function.

Endometrial response following percutaneous estrogen replacement therapy. A morphometric investigation.

The endometrial response in 10 postmenopausal women receiving estrogen replacement therapy was evaluated morphologically and quantified by morphometric analysis. During 6 months of cyclic treatment with percutaneous estradiol-17 beta, 3 mg daily, the mean relative endometrial gland volume increased from 10% to 40%. In each individual woman this morphometric parameter was significantly correlated to the serum concentration of estradiol-17 beta. The decline in FSH level during treatment showed no significant correlation to the endometrial response or the estrogen level. In some endometrial samples from women during treatment, glands with incomplete epithelial lining and rows of glandular epithelial cells were observed. It is suggested that these phenomena represent early forms of glandular development.

Percutaneous estrogen replacement therapy. Effects on circulating estrogens, gonadotropins and prolactin.

A percutaneous gel containing 0.6 mg/g of estradiol-17 beta was used for cyclic replacement therapy in 19 postmenopausal women. Significantly increased serum concentrations of estradiol-17 beta, unconjugated estrone, and total estrone were recorded during 6 months of treatment. In contrast to oral treatment the quotient of estrone/estradiol-17 beta was maintained and even reduced during therapy. Significant gonadotropin inhibition was recorded and the estrogenic potency of 3 mg percutaneous estradiol-17 beta was similar to that of oral estradiol-17 beta 2 mg and 2.5 mg oral estrone sulphate. Prolactin levels remained constant during treatment. Therapy was effective in abolishing hot flushes in 17 out of the 19 women treated. The therapy was well accepted by the volunteers. Seventeen out of 19 women stated that the gel was easy to use in everyday life. Topic application may develop into an alternative treatment for climacteric complaints and may even have some metabolic advantages over oral treatment.

Danazol and gestagen displacement of testosterone and influence on sex-hormone-binding globulin capacity.

The mechanism of action of danazol is poorly understood, but this testosterone (T) derivate is frequently used in the clinical treatment of endometriosis, and its tendency to androgenic/anabolic side effects is well known. The interaction of danazol with T binding to sex-hormone-binding globulin (SHBG) was studied with the use of an aqueous two-phase system with polyethylene glycol (PEG) and dextran for equilibrium partition. Competitive binding studies were also performed with norethisterone (NET), d-norgestrel (d-Ng), medroxyprogesterone acetate (MPA), and tamoxifen (TMX). Danazol, d-Ng, and NET were found to exert a marked T displacing activity, while MPA and TMX had no significant effect. The low values for SHBG binding capacity that were found during danazol therapy mainly reflect occupation of binding sites by danazol and to a lesser degree a real decrease in protein concentration. It was calculated that during treatment the total SHBG capacity in serum is approximately 20 times exceeded. Therapeutic danazol serum levels are 1000 times those of normal female total T levels; and since the affinity to SHBG for danazol was found to be 1/20 that to T one should conclude an almost total occupation of binding sites. The endocrine effects of danazol might be interpreted in terms of T displacement and as a consequence of increased levels of free T during therapy.

A comparative study of the estrogenic effects of tamoxifen and 17 beta-estradiol in postmenopausal women.

The effects of tamoxifen and 17 beta-estradiol on the levels of FSH, PRL, and pregnancy zone protein were compared in two groups of postmenopausal women. Seventeen women with breast cancer were treated with tamoxifen (20 mg, twice a day). Fourteen women with climacteric complaints were given 17 beta-estradiol (2 mg, daily). A close parallelism between the effects of 17 beta-estradiol and the antiestrogen was obtained in all three markers studied. The percent decreases in FSH after 1 month were 29 and 44 and, after 3 months, 26 and 34 in the tamoxifen and estradiol groups, respectively. The decreases in PRL after 1 and 3 months of treatment with tamoxifen were 36% and 71%, and 19% and 31% after treatment with estradiol. Both treatments increased PZP serum levels, tamoxifen by 32% and 44% and estradiol by 55% and 70% after 1 and 3 months. Thus, tamoxifen was found to exert weak estrogenic effects in postmenopausal women.

A comparative longitudinal study on sex hormone binding globulin capacity during estrogen replacement therapy.

An aqueous two-phase equilibrium partition system was used to assay SHBG-binding capacity. Sera from groups of postmenopausal women before and during unopposed estrogen replacement therapy were analyzed. The induction of SHBG showed considerable differences between different estrogens. Ethinyl-estradiol in a daily dose of 0.05 mg gave a 70% increase in the serum concentration of this liver derived protein. Estradiol-17 beta, 2 mg daily and estrone sulphate 1.25 mg gave moderate changes, whereas estriol in different doses had no effect. SHBG induction may reflect estrogen overtreatment.

Estrogenic potency of oral replacement therapy estimated by the induction of pregnancy zone protein.

The induction of a highly estrogen-inducible plasma protein, the pregnancy zone protein/pregnancy associated alpha 2-globulin (PZP/PA alpha 2 G), was used to design a sensitive method to quantify and compare the potency of various estrogens commonly used in clinical practice. Serum PZP levels were followed in 100 post-menopausal women during 6 months' estrogen replacement therapy. Ethinyl estradiol caused more marked changes than the natural estrogens. Conjugated estrogens were more potent than estrone sulphate and estradiol-17 beta which had similar values. Estriol, irrespective of daily dosage, exerted a negative effect. The following sequence of equipotency was calculated: ethinyl estradiol = 100 x conjugated estrogens = 450 x estrone sulphate = 500 x estradiol-17 beta = 650 x estradiol valerate. These data were compared with other estimates of estrogenic potency from the literature. Compared with other clinical methods, PZP induction offers several advantages. Factors such as intestinal absorption, protein binding and intracellular metabolism are included in the net result of an increased protein synthesis which is easily followed in patients' sera during therapy.

Effects of various oestrogens on circulating androgens and cortisol during replacement therapy in post-menopausal women.

The influence of various oestrogens during unopposed replacement therapy on circulating androgens and cortisol was studied in 65 post-menopausal women. As dose dependent decrease in dehydroepiandrosterone sulphate (DHAS) was found. Ethinyloestradiol (0.05 mg daily) already gave a significant decrease after 1 mth of treatment. The decline following 17 beta-oestradiol (2 mg) and oestrone sulphate (2.5 mg) was less pronounced. Oestriol (6 mg daily) had no effect. Ethinyloestradiol also increased the levels of total cortisol and testosterone, probable because of serum protein induction, while 17 beta-oestradiol had no significant effect. Serum levels of androstenedione remained unchanged during therapy.

Effects of sex hormone binding globulin capacity and pregnancy zone protein of treatment with combinations of ethinyl-oestradiol and norethisterone.

Sex hormone binding globulin (SHBG) and pregnancy zone protein (PZP) are two highly oestrogen-inducible serum proteins. SHBG capacity and PZP level were measured in 49 women treated with three different combinations of ethinyloestradiol and norethisterone. SHBG capacity and PZP were measured before and after 6 mth of treatment and both serum factors significantly increased during treatment for all three groups. PZP induction was found to be more sensitive and mainly to reflect the oestrogen component of a combined preparation while SHBG capacity was more sensitive to the modulating effect of the progestogen.