Reappraisal of progestins in endometriosis therapy.
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Endometriosis↗
Biomedical subjects
A Kauppila
Publications and source records attributed to A Kauppila.
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.
Administration, Oral↗
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.
Aged↗
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.
Administration, Cutaneous↗
The effect of postmenopause and postmenopausal HRT on measured voice values and vocal symptoms.
OBJECTIVES: To study the effect of postmenopause and postmenopausal hormone replacement therapy (HRT) on the measured fundamental frequency (F0) and sound pressure level (SPL) of sustained phonation and speaking voice samples and on subjective vocal/laryngeal symptoms. METHODS: Forty-three postmenopausal women (mean age 51.6) were divided into three groups: a group with no HRT, an estrogen group (daily oral dose of 2 mg of estradiol valerate), and an estrogen-progestin group (daily oral dose of 2 mg of 17-B-estradiol and 1 mg of northisterone acetate). Voice measurements were made before and after 1 year of treatment. Subjective symptoms were registered using a questionnaire. RESULTS: The mean F0 and SPL decreased significantly in the group with no HRT in spontaneous speech and reading samples as did SPL in the normal phonation sample. In both groups with HRT, the mean F0 decreased significantly only in the spontaneous speech sample and the decrease was smaller than in the group with no HRT. The mean SPL decrease in the estrogen group was significant in the normal phonation sample while in the estrogen-progestin group it was significant in both the normal phonation and the reading sample. The number of subjective symptoms was smallest in the estrogen group. CONCLUSIONS: The changes in the measured voice values and the subjective symptoms experienced suggest that at least the early postmenopausal years are associated with vocal changes and that HRT counteracts this phenomenon. This seems to be more pronounced with estrogen than with a combination of estrogen and progestin.
Cohort Studies↗
Systemic therapy with estrogen or estrogen with progestin has no effect on skin collagen in postmenopausal women.
OBJECTIVES: To investigate the effect of estrogen alone or combined with progestin on the amount and synthesis of skin collagen in postmenopausal women. METHODS: Forty-three early postmenopausal women were enrolled into this open, non-randomized parallel-groups study. Fifteen women received a continuous oral dose of 2 mg of 17 beta-estradiol and 1 mg of norethisterone acetate daily and 14 women an oral dose of 2 mg estradiol valerate daily. Fourteen subjects served as controls. The histology and type I and III procollagen immunohistochemistry of the skin, skin thickness, the amount of total collagen determined by a colorimetric method and the synthesis of type I and III collagens determined by analysing procollagen propeptides in the suction blister fluid were studied before the treatment and at 6 and 12 months. The proportional area of elastic fibers and the thickness of the epidermis were assessed from the sections obtained before the treatment and at 12 months, with computerized image analysis. RESULTS: Skin thickness, the amount and rate of collagen synthesis, the proportional area of elastic fibers and the thickness of the epidermis were not affected by either 17 beta-estradiol and 1 mg of norethisterone acetate or 2 mg of estradiol valerate. No histological or immunohistological changes were detected in the skin specimens during the 12-month treatment period compared to the baseline or to the skin specimens of the control group. CONCLUSIONS: A 1-year treatment with systemic estrogen alone or combined with progestin does not change the amount of collagen or the rate of collagen synthesis in postmenopausal women.
Administration, Oral↗
The clinical outcome in pregnancies of grand grand multiparous women.
OBJECTIVE: To longitudinally evaluate maternal and neonatal complications with relation to birth order, with specific emphasis on grand grand multiparity (at least 10th para). METHODS: The maternal and neonatal outcome of 1200 pregnancies/deliveries in 96 grand grand multiparas was longitudinally investigated in 4 stages of the mothers' life: the primiparas, the multiparas (2nd-5th paras), the grand multiparas (6th-9th paras) and the grand grand multiparas stage. RESULTS: The frequency of hypertension, diabetes, placental complications, operative interventions at delivery, macrosomic infants, chromosomal abbreviations and fetal/neonatal anomalies increased with increasing birth order, being at a maximum in grand grand multiparas. The preterm delivery and perinatal mortality rate did not differ between the 3 groups of multiparas. Perinatal outcome was good in each group. CONCLUSIONS: Grand grand multiparity carries the risk of hypertensive and diabetic complications, which, in turn, often lead to induced or operative deliveries and placental complications. However, grand grand multiparity is not a major problem in societies with a good maternal health care system.
Apgar Score↗
Luteinizing hormone-releasing hormone agonist triptorelin in combination with cytotoxic chemotherapy in patients with advanced ovarian carcinoma. A prospective double blind randomized trial. Decapeptyl Ovarian Cancer Study Group.
BACKGROUND: Several lines of evidence suggest that the proliferation of ovarian carcinoma might be stimulated by gonadotrophins. A number of Phase I/Phase II clinical trials have reported that the suppression of endogenous luteinizing hormone and follicle-stimulating hormone secretion by luteinizing hormone-releasing hormone (LHRH) analogs induced objective remissions and/or disease stabilization in 10-30% of patients with advanced refractory ovarian carcinoma. The current study was performed to evaluate whether the addition of LHRH agonist treatment to standard platinum-based chemotherapy could prolong survival of patients with surgically treated Stage III or IV epithelial ovarian carcinoma. METHODS: One hundred and thirty-five patients with Stage III or IV epithelial ovarian carcinoma participated in this prospective randomized double blind trial. After cytoreductive surgery, 69 patients received monthly injections of a depot preparation of the LHRH agonist [D-Trp6] LHRH (triptorelin, 3.75 mg) and 66 patients received placebo until their deaths or termination of trial, respectively. All patients were treated with a standard platinum-based chemotherapy, and, if necessary, with second- or third-line cytotoxic regimens. RESULTS: Endogenous gonadotrophins were reliably suppressed in patients treated with triptorelin. However, their progression free and overall survival were not significantly different from that of patients receiving placebo injections (statistical power > 80% for a difference between both groups of > or = 20%). CONCLUSIONS: The results of this trial suggest that the suppression of endogenous gonadotrophins by conventional doses of an LHRH agonist produces no relevant beneficial effects in patients with advanced ovarian carcinoma who receive standard surgical cytoreduction and cytotoxic chemotherapy.
Adult↗
Medroxyprogesterone acetate supplementation diminishes the hypoestrogenic side effects of gonadotropin-releasing hormone agonist without changing its efficacy in endometriosis.
OBJECTIVE: To examine the effects of concomitant use of goserelin and medroxyprogesterone acetate (MPA) in the treatment of endometriosis. DESIGN: Thirty-eight women with laparoscopically confirmed endometriosis were treated with once-a-month s.c. injections of goserelin acetate 3.6 mg (Zoladex depot; Zeneca Pharmaceutics, Cheshire, United Kingdom) randomly combined with either MPA (100 mg daily; n = 19) or a placebo (one tablet daily; n = 19) in a double-blind trial. Symptoms and side effects were monitored for a treatment period of 6 months and a follow-up period of 6 months. Blood and urine samples were collected for the assessment of endocrine and biochemical parameters. A second-look laparoscopy was performed 6 months after the treatment in 29 women. RESULTS: The extent of endometriosis was diminished similarly in both treatment groups, as were pelvic symptoms. Fewer women in the MPA group had hot flushes and sweating at 3 and 6 months of treatment. Sex hormone-binding globulin decreased in the MPA group but not in the placebo group. Consequently, the E2 index (E2/SHBG X 100), reflecting the free fraction of E2, fell more in the placebo group than it did in the MPA group. The increased urinary excretion of calcium observed during placebo treatment was prevented by MPA. CONCLUSION: High-dose MPA combined with a GnRH agonist (GnRH-A) diminished some antiestrogenic effects of the agonist. A reduction in hypoestrogenic side effects and a possible bone-sparing effect can be regarded as beneficial, especially as the good effect of the GnRH-a on endometriotic implants and pelvic symptoms prevailed.
Adult↗
Seasonal changes in pituitary function: amplification of midfollicular luteinizing hormone secretion during the dark season.
OBJECTIVE: To analyze the effect of season on the pulsatility of gonadotropin secretion in women living in an area with a large annual variability in daylight length. DESIGN: A prospective study. Pulse studies were carried out in each subject during both the dark and light season. SETTING: The gynecologic endocrine research unit of the University Central Hospital of Oulu. PARTICIPANTS: Eleven ovulatory, healthy women volunteering for the study. INTERVENTIONS: Serum samples were collected at 10-minute intervals for 6 hours on days 7 to 9 of the cycle. MAIN OUTCOME MEASURES: Serum LH and FSH concentrations were measured and the data were analyzed with an algorithm computer-based program. RESULTS: The mean area of LH pulses analyzed was significantly higher during the dark season than the light season (49.1 +/- 3.1 versus 38.5 +/- 1.7 mIU/mL; conversion factor to SI unit, 1.00), while in the amplitude (1.9 +/- 0.1 versus 1.8 +/- 0.1 mIU/mL), number of pulses (5.2 +/- 0.3 versus 4.4 +/- 0.6), and the mean level (9.6 +/- 0.5 versus 9.4 +/- 0.9 mIU/mL) the difference did not reach statistical significance. The number (5.2 +/- 0.5 versus 5.2 +/- 0.4,), amplitude (1.0 +/- 0.05 versus 1.1 +/- 0.07 mIU/mL; conversion factor to SI unit, 1.00), area (29.9 +/- 2.4 versus 29.6 +/- 3.1 mIU/mL), and the mean level of FSH (5.4 +/- 0.6 versus 6.0 +/- 0.8 mIU/mL) during the dark and light seasons were identical, showing no seasonal variability. CONCLUSIONS: The results indicate increased pituitary LH secretion in the midfollicular phase during the dark season that may be related to increased melatonin secretion and decreased ovarian activity at this time of the year.
Adult↗
Decrease in melatonin precedes follicle-stimulating hormone increase during perimenopause.
Melatonin, the hormone of the pineal gland, which in animal studies has been found to inhibit aging processes, is secreted in smaller amounts towards senescence. Menopause, an aging process in women, is known to be associated with typical changes in gonadotropin and sex steroid secretion. Our main objective was to study the possible role of melatonin in the hormonal regulation of menopause. This study focused on detailed changes in melatonin and follicle-stimulating hormone (FSH) secretion cross-sectionally in pre- to postmenopausal females. Special attention was paid to females aged around 50 years, which is the mean menopausal age. Seventy-seven healthy female volunteers aged 30-75 years were the subjects of this study. Melatonin was measured radioimmunologically from nocturnal urine collected between 20.00 and 08.00 h, and FSH and melatonin from blood samples taken at 0.900 h. Nocturnal urinary excretion of melatonin was found to decline significantly from premenopause to postmenopause. The youngest premenopausal women (age group 30-39 years) excreted the highest amounts of melatonin (21.2 +/- 2.2 pmol/h, mean +/- SEM, N = 17). In the age group 40-44 years the excretion declined by 41% (p < 0.05). The second significant decline (35%, p < 0.05) took place between the age groups 50-54 years and 55-59 years. A declining trend as a function of age was also seen in morning serum melatonin. Serum FSH rose sharply to high levels before the age of 50 (p < 0.01) and remained at a high level thereafter. Urinary melatonin correlated negatively with serum FSH (r = -0.32, p < 0.05). In conclusion, the inverse changes in melatonin and FSH secretion during the perimenopausal years, with the sharpest decline in nocturnal excretion of melatonin far before menopause, suggest that melatonin may be permissively linked to the initiation of menopause.
Adult↗
[The role of progestin in menopausal hormonal replacement therapy].
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Adult↗
Expression of mRNAs for type I and type III procollagens in serous ovarian cystadenomas and cystadenocarcinomas.
Malignant ovarian tumors induce a strong fibro-proliferative reaction characterized by the active production of type I and type III procollagen both locally in the ovary as well as more remotely in the peritoneal cavity. Our purpose was to determine the origin of the increased collagen production observed in serous ovarian tumors with different histological grades of malignancy, ie, whether the malignant cells or the stromal fibroblasts are responsible for the synthesis of collagen fibers. We visualized the mRNAs corresponding to the pro alpha 1(I) and pro alpha 2(I) chains of type I procollagen and the pro alpha 1(III) chain of type III procollagen by in situ hybridization. Strong signals for both chains of type I procollagen were seen in stromal fibroblasts next to tumor cell islets, whereas the reaction was weak or absent near benign ovarian cysts. In poorly differentiated tumors, the signals were particularly abundant and occasionally also seen in the neoplastic cells themselves. Type III procollagen mRNA expression was similar, although somewhat less distinct. These findings indicate that the production of interstitial procollagens is related to the degree of malignancy and neoplastic activity of tumors. The formation of collagen in well differentiated ovarian tumors is a function of stromal fibroblasts, whereas in poorly differentiated tumors, aberrant expression of one or several chains of type I and type III procollagens in the neoplastic cells is also likely to take place.
Antisense Elements (Genetics)↗
Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms.
BACKGROUND: Type I collagen is a major constituent of the interstitial connective tissue. Although ovarian carcinoma is known to induce the expression of type I collagen in the peritoneal cavity, the distribution and metabolic activity of this collagen in ovarian tumor tissue are not known. METHODS: The distributions and staining intensities of different molecular forms of type I collagen in ovarian neoplasms were studied immunohistochemically with antibodies to the aminoterminal propeptide of type I procollagen (PINP) and the cross-linked carboxyterminal telopeptide of type I collagen (ICTP), reflecting the presence of newly synthesized and old, cross-linked type I collagen, respectively. RESULTS: A regular pattern of moderately staining, relatively uniform fibers was observed in the stroma of benign serous and mucinous cystadenomas, indicating limited participation in tumor growth. The staining was accentuated subepithelially in borderline epithelial neoplasms and in well differentiated cystadenocarcinomas, suggesting induction of the stromal collagen synthesis by the tumor cells. Fewer degraded collagen fibers were found in moderately differentiated carcinomas, most likely because of enzymatic degradation of the stroma surrounding the neoplasms during tumor spread. Strongly staining, irregular collagen fibers occurred closely around islets of tumor cells in undifferentiated malignant neoplasms and in metastases of ovarian carcinomas; also, intracellular staining was present in part of the malignant cells. In most cases, the staining reactions obtained with the two different antibodies were similar, probably indicating rapid processing of the newly synthesized type I collagen (indicated by PINP) to a maturely cross-linked form (indicated by ICTP). CONCLUSIONS: Synthetic and degradative processes are typical of the collagenous matrix in malignant ovarian tumors. Aberrant expression of type I collagen may occur in anaplastic ovarian carcinomas.
Adult↗
Comparison between the effects of tamoxifen and toremifene on the uterus in postmenopausal breast cancer patients.
Antiestrogens have been widely used in the treatment of breast cancer patients. We wanted to compare the uteral and vaginal effects of tamoxifen to those of toremifene. Thirty-one gynecologically asymptomatic postmenopausal breast cancer patients with an intact uterus were randomized to receive 20 mg of tamoxifen (N = 16) or 60 mg of toremifene (N = 15) as an adjuvant treatment. Gynecological examination with vaginal ultrasonography, Pap smear, endometrial biopsy, hysteroscopy, and curettage was performed before the treatment, and at 6 and 12 months of treatment. Endometrial thickness was found to increase significantly during the treatment to the same extent in both groups. Proliferation or other estrogenic effects in the endometrium were observed in 8 of 14 patients in the tamoxifen group and in 3 of 10 patients in the toremifene group. Three polyps occurred and previously present uterine fibroids increased in size in 3 of 10 patients during the study. Estrogenic changes in Pap smear were observed in all patients. There was no significant difference between tamoxifen and toremifene in any of the parameters investigated. Our results suggest that tamoxifen and toremifene produce comparable estrogenic effects in the uterus and vagina.
Adult↗
Endometrial adenocarcinoma complicated by malignant pericardial effusion.
A case of malignant pericardial effusion associated with endometrial adenocarcinoma is presented. A total abdominal hysterectomy with bilateral salpingo-oophorectomy and partial omentectomy was performed 8 months before the occurrence of cardiac tamponade. The treatment of malignant pericardial effusion consisted of emergency pericardiocentesis and systemic chemotherapy and a clinical response for 6 months was achieved.
Adenocarcinoma↗
Macrophage colony-stimulating factor 1, a clinically useful tumor marker in endometrial adenocarcinoma: comparison with CA 125 and the aminoterminal propeptide of type III procollagen.
OBJECTIVE: We investigated the clinical utility of macrophage colony-stimulating factor 1 versus CA 125 and the aminoterminal propeptide of type III procollagen in endometrial carcinoma. STUDY DESIGN: Serum levels of the three substances were measured in 159 patients with untreated endometrial adenocarcinoma and in 24 patients treated with cytotoxic chemotherapy for recurrent endometrial adenocarcinoma. RESULTS: Initial concentrations of colony-stimulating factor 1, CA 125, and the aminoterminal peptide of type III procollagen were above the normal range in 73%, 11%, and 27%, respectively, of the patients. Colony-stimulating factor 1 levels correlated with those of the aminoterminal peptide of type III procollagen (r = 0.3, p = 0.002) and CA 125 (r = 0.20, p = 0.036) in the total group and with those of the aminoterminal peptide of type III procollagen in stage I and II patients (r = 0.3, p = 0.0023). Colony-stimulating factor 1 levels correlated significantly with tumor grade, whereas those of CA 125 and the aminoterminal peptide of type III procollagen correlated more closely with clinical stage. Mean colony-stimulating factor 1 levels (9.6 vs 7.7 ng/ml, p = 0.04) and the frequency of elevated CA 125 levels (31% vs 8%, p = 0.048) were higher in patients with poor prognosis than in those with good prognosis. Colony-stimulating factor 1, the aminoterminal peptide of type III procollagen, and CA 125 levels were useful in monitoring clinical behavior of the disease in 88%, 79%, and 63% of the cases, respectively. Levels of all three markers rose with disease progression, whereas colony-stimulating factor 1 and the aminoterminal peptide of type III procollagen fell with clinical responses to therapy. CONCLUSION: Elevated serum colony-stimulating factor 1 levels were the most accurate indicator of the presence and activity (progression, stabilization, or regression) of primary or recurrent disease. Accuracy was not further enhanced by measurement of CA 125 or the aminoterminal peptide of type III procollagen levels.
Adenocarcinoma↗