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.

Percutaneous estradiol gel with an intrauterine levonorgestrel releasing device or natural progesterone in hormone replacement therapy.

OBJECTIVE: To evaluate the bleeding patterns and clinical compliance associated with postmenopausal amenorrhea-inducing forms of hormone replacement therapy using either percutaneous estradiol-gel and a levonorgestrel-releasing intrauterine device or an oral/vaginal natural progesterone. METHODS: Sixty postmenopausal women with an intact uterus were followed over 12 months in this open, non-randomised, parallel group study. All patients continuously received a gel containing 1.5 mg of estradiol daily. The women were divided into three groups on the basis of progestin administration. Twenty women (group I) had a levonorgestrel-releasing device (LNG-IUD) inserted at the beginning of the study. Twenty-one women (group II) received oral natural micronised progesterone (oral P) 100 mg daily during 25 calendar days each month, and 19 women (group III) used vaginal natural micronised progesterone (vaginal P) 100-200 mg daily during 25 calendar days each month (higher dose if spotting occurred). Clinic visits were at 0, 3, 6 and 12 months. Bleeding patterns were recorded by the patient in a diary and clinical compliance was evaluated at control visits during the treatment. Symptoms were recorded using a modified Kuppermann index. The serum estradiol concentration was determined at the 0, 6 and 12 month control visits. RESULTS: 80% (n = 16) of the patients in the LNG-IUD group, 67% (n = 14) in the oral P group II and 53% (n = 10) in the vaginal P group were without bleeding at 12 months. Spotting was common during the first 3 months. Symptom relief was good in each group. The LNG-IUD did not cause any serious side-effects. Compliance was good for LNG-IUD and oral progesterone but not for vaginal progesterone. CONCLUSIONS: Percutaneous estradiol-gel associated with LNG-IUD is an appropriate method of hormone replacement therapy. The combination of oral natural progesterone with estradiol-gel is also useful, although bleeding episodes complicated the treatment in one third of the patients. The vaginal administration of natural progesterone was impractical due to bleeding disorders.

Comparison of three serum assays for bone collagen formation during postmenopausal estrogen-progestin therapy.

Postmenopausal hormone replacement therapy (HRT) lowers the turnover rate of the mineralized bone matrix, the predominant organic component of which is type I collagen. The effect of estrogen on bone metabolism has been monitored by measuring the circulating concentration of the carboxy-terminal propeptide of type I procollagen (PICP), which decreases during HRT. We have recently developed assays for the intact amino-terminal propeptide (PINP) of type I procollagen, a protein set free from the other end of the same gene product. PICP and PINP, both derived from the synthesis of type I collagen, but differing in their further metabolism, were assessed in 47 postmenopausal women, aged 45-66 years, undergoing postmenopausal HRT. Estradiol-gel applied daily was combined to a continuous progestin administered by three different routes. Serum samples obtained before the treatment and 6 and 12 months after its commencement were analyzed for PICP, PINP, PINP Col 1 (assay variant measuring also the degradation product of PINP) and PIIINP (amino-terminal propeptide of type III procollagen). During HRT the circulating concentration of PICP decreased by 20%, that of PINP by 42% and that of PINP Col 1 by 32% in 12 months. The correlation between the two propeptides, which was 0.676 before the treatment, increased to 0.851 in 6 months and to 0.815 in 12 months. The correlations between PINP and PINP Col 1 were 0.872 before the treatment and increased to 0.925 and 0.941 after 6 and 12 months of treatment, respectively. The serum concentration of PIIINP, which reflects the turnover of the soft tissue collagens, did not change remarkably. Our findings indicate that the intact PINP is a more dynamic marker of bone metabolism than PICP and can therefore be recommended as a marker reflecting the effect of estrogen on bone collagen formation during HRT.

Insulin-like growth factor-binding protein-1: a biochemical marker of endometrial response to progestin during hormone replacement therapy.

OBJECTIVES: To compare immunohistochemical localization of insulin-like growth factor binding protein-1 (IGFBP-1) in endometrial stromal cells with endometrial morphology during three regimens of continuous combined hormone replacement therapy. METHODS: Endometrial samples for morphological examination and immunohistochemical staining with monoclonal antibody against IGFBP-1 were obtained from 30 menopausal women before treatment and after 12 and 24 months of continuous combined hormone replacement therapy. All women received percutaneous estradiolgel releasing 1.5 mg estradiol daily. Regarding progestins, patients were divided into three groups: one group (n = 15) had a 20 micrograms/24 h levonorgestrel-releasing intrauterine device (LNG-IUD); the women in the other two groups received micronised natural progesterone either 100 mg orally (n = 7) or 100-200 mg vaginally (n = 8) daily, 25 days per calendar month. RESULTS: Before treatment the endometrium of all women was atrophic or subatrophic and no IGFBP-1 could be detected in any of the samples which contained enough stromal cells for evaluation. After 12 and 24 months of treatment, epithelial atrophy with decidual transformation in stroma was detected in all specimens in the LNG-IUD group, and IGFBP-1 was localized in decidualized stromal cells in all samples. In the other two groups, no signs of progestin effect were detected by microscopic examination in any of the endometrial samples and IGFBP-1 staining was completely negative in all of them. CONCLUSION: A striking difference occurred in both morphological and biochemical response in the endometrium of women treated with LNG-IUD compared with those receiving oral or vaginal micronised progesterone during continuous combined HRT. Micronised progesterone at doses used in this study turned out to be ineffective to prevent the proliferative effect of estrogen. Immunohistochemical localization of IGFBP-1 in endometrial stromal cells strongly correlated with decidual reaction in all endometrial specimens exposed to LNG-IUD, suggesting that the immunostaining of IGFBP-1 can be used as a means of assessing the strength of progestin effect in the endometrium during HRT.

Supplementation with selenium, vitamin E and their combination in gynaecological cancer during cytotoxic chemotherapy.

The biochemical responses to 8-week supplementary treatment with selenium and/or vitamin E were evaluated in 41 patients with gynaecological cancer during cytotoxic chemotherapy, in Finland, a selenium-deficient country. After the control course of 1-day treatment with cytostat agents, 11 patients received a combination of selenium and vitamin E (sodium selenate, 200 micrograms/day + vitamin E, 300 mg/day), 11 received selenium (sodium selenate, 200 micrograms/day) and seven received vitamin E (300 mg/day) as supplementary therapy, while 12 patients had no supplementary drugs. Sodium selenate alone and combined with vitamin E significantly increased the serum selenium levels, but the activity of serum glutathione peroxidase (GSH-Px) increased significantly only in the selenium- and vitamin E-treated patients with low initial GSH-Px activity. The cytotoxic chemotherapy did not change the activity of GSH-Px, while the concentrations of lipid peroxides decreased. Sodium selenate alone or with vitamin E did not modify this decrease. Sodium selenate alone significantly decreased the capacity of the platelets to produce thromboxane A2; it increased high-density lipoprotein cholesterol levels and prevented the cytotoxic-chemotherapy-associated increase of creatine kinase. Selenium supplementation might thus be beneficial during cytotoxic chemotherapy in ovarian cancer patients with low selenium levels.

Serum selenium and thromboxane in patients with gynaecological cancer.

To explore the relationships between the antioxidant selenium and pro-aggregatory thromboxane A2 in patients with gynaecological cancer, we measured the serum concentrations of selenium and the production of thromboxane B2 (TxB2, a stable metabolite of thromboxane A2) by the aggregating platelets in patients with endometrial (n = 35), ovarian (n = 30) and cervical cancer (n = 25), and in 32 control women. The selenium concentration in endometrial (1.14 +/- 0.04 mumol/l; mean +/- SE), ovarian (0.96 +/- 0.04 mumol/l) and cervical cancer (0.97 +/- 0.06 mumol/l) was significantly lower than in control subjects (1.26 +/- 0.03 mumol/l). The release of TxB2 into serum during spontaneous clotting of the blood was significantly increased in ovarian cancer (229.2 +/- 15.9 ng/ml), decreased in endometrial cancer (142.6 +/- 12.4 ng/ml) and normal in cervical cancer (185.9 +/- 14.8 ng/ml) as compared with control subjects (185.9 +/- 11.9 ng/ml). The levels of selenium and TxB2 did not correlate with each other in the whole series or in any subgroup. Thus, selenium does not seem to be an important determinant in the biosynthesis of TxB2 in patients with gynaecological malignancy.

Annual variation of serum selenium in patients with gynaecological cancer during 1978-1983 in Finland, a low selenium area.

To explore the relationship between selenium deficiency in cancer and nutritional factors, we measured the serum concentrations of selenium in 1978-1983 in patients with gynaecological cancer (N = 277) and correlated these with the estimated daily intake of selenium, which varies in Finland depending on the proportion of selenium-rich imported grain. The selenium concentration increased significantly from 1978-1979 to 1982 in the series of all cancer patients (p less than 0.001) and separately in cases of cervical (p less than 0.001) and endometrial cancer (p less than 0.02), parallel to the increased daily intake of selenium. The serum level of selenium decreased in 1983, when the import of selenium-rich grain was reduced. Low serum selenium in cancer patients thus seems to be mainly dependent on dietary factors.

Serum selenium and glutathione peroxidase, and plasma lipid peroxides in uterine, ovarian or vulvar cancer, and their responses to antioxidants in patients with ovarian cancer.

The concentrations of serum selenium and plasma lipid peroxides, and the activity of serum glutathione peroxidase (GSH-Px) were measured before any therapy in patients suffering from uterine, ovarian or vulvar cancer, and in association with 1-day combination cytotoxic chemotherapy of ovarian cancer following 1-week supplementation with selenium (96 micrograms/day), vitamin E (300 mg/day), selenium and vitamin E, or placebo. Patients with gynaecological cancer (N = 44) had lower serum concentration of selenium (1.15 +/- 0.04 S.E. mumol/l; P less than 0.05) and serum activity of GSH-Px (404 +/- 13 units/l, P less than 0.01) than the control subjects (N = 56; 1.25 +/- 0.03 mumol/l and 444 +/- 8 units/l, respectively). In association with cytotoxic chemotherapy selenium alone (P less than 0.05), vitamin E alone (P less than 0.05) and both of them together (P less than 0.001) decreased the plasma concentration of lipid peroxides, and the combination of selenium and vitamin E also increased the activity of serum GSH-Px (P less than 0.01). During placebo, cytotoxic chemotherapy did not affect plasma lipid peroxides but it decreased (P less than 0.001) the activity of GSH-Px. Selenium inhibited this effect. Our data suggest that antioxidative mechanisms of patients with gynaecological cancer may be defective and that treatment with selenium and vitamin E results in changes of biochemical factors related to lipid peroxidation.

Serum selenium in patients with ovarian cancer during and after therapy.

Serum concentrations of selenium were determined by atomic absorption spectrophotometry in 40 patients with ovarian cancer in association with and after surgical and cytostatic therapy. Patients with ovarian cancer had significantly (p less than 0.001) lower serum concentrations (mean +/- SE) of selenium (0.93 +/- 0.04 mumol/l) than age-, weight- and place of residence-matched control subjects (1.22 +/- 0.03 mumol/l). In clinical stage IV disease there was a lower serum level of selenium (0.82 +/- 0.07 mumol/l) than in clinical stages I and II combined (1.00 +/- 0.04 mumol/l). Serum selenium concentrations also showed a tendency to follow the outcome of the disease; an increase in patients with remission and a decrease in patients with progressive disease, probably because of nutritional reasons.

Hepatic impairment during simultaneous administration of medroxyprogesterone acetate and tamoxifen in the treatment of endometrial and ovarian carcinoma.

Simultaneous administration of medroxyprogesterone acetate (MPA) and tamoxifen markedly elevated the serum alanine and aspartate aminotransferase activities in 4 out of 30 patients with endometrial or ovarian carcinoma; and also slightly increased the activities of gamma-glutamyl transferase in 2 of the patients. These pathological changes spontaneously returned to normal in 1 patient, and after the cessation of tamoxifen or tamoxifen plus MPA treatment in 3 patients. This kind of hepatic impairment was thought to be caused by reversible damage of liver cells possibly associated with slight intrahepatic cholestasis. It is suggested that special attention be paid to liver function during simultaneous MPA and tamoxifen administration; in case of adverse liver reaction during the combined treatment, a formula of sequential administration of the drugs could be implemented.

Low serum selenium concentration in patients with cervical or endometrial cancer.

Serum concentrations of selenium were determined in 37 patients with cervical and 64 patients with endometrial cancer. The patients had lower (P less than 0.001) serum concentrations of selenium than the age-, weight- and place of residence-matched paired control women. There was no difference in the selenium concentration between various age groups or different clinical stages of cervical or endometrial cancer. A low serum concentration of selenium might be a contributing factor in uterine carcinogenesis.