Hyperprolactinemia complicating juvenile granulosa cell tumor of the ovary.

BACKGROUND: Granulosa cell tumors are known to be hormonally active. They usually produce estrogen and inhibin, and the serum inhibin level is often considered a useful tumor marker during the follow-up of this illness. CASE: We present a case of malignant juvenile granulosa cell tumor associated with hyperprolactinemia. In our patient, the serum prolactin concentration closely reflected the behavior of the disease. CONCLUSION: Our findings are consistent with the assumption that prolactin was a tumor marker in this patient.

The levonorgestrel intrauterine system in menopausal hormone replacement therapy: five-year experience.

OBJECTIVE: To study the long-term effects (5 years) of intrauterine levonorgestrel administration as the progestin part of continuous combined postmenopausal hormone replacement therapy. DESIGN: Prospective clinical study. SETTING: Department of obstetrics and gynecology at a central hospital. PATIENT(S): Twenty postmenopausal women with an intact uterus who had no contraindications to hormone replacement therapy and who wanted to take amenorrhea-inducing hormone replacement therapy to relieve their climacteric symptoms. INTERVENTION(S): A percutaneous E2 gel containing 1.5 mg of E2 was administered daily and a levonorgestrel-releasing intrauterine device was used. Endometrial thickness was measured by vaginal ultrasonography. Endometrial sampling was performed yearly. MAIN OUTCOME MEASURE(S): Clinical compliance, profiles of bleeding, and endometrial thickness and morphology were monitored during 5 years of follow-up. RESULT(S): Eighteen women completed 1 year of follow-up. Fifteen of these women were willing to continue the study, and 12 of them completed 5 years of follow-up. Spotting was frequent during the first 6 months of the study and declined thereafter. At 1 year, 80% of the women were totally amenorrheic. Of the 15 women who continued the study, 12 were totally amenorrheic and 3 had problems with bleeding. The mean endometrial thickness was < or = 3 mm during the study. Endometrial morphology showed epithelial atrophy accompanied by decidualization of the stroma in all 12 of the women who were followed up for 5 years. CONCLUSION(S): Intrauterine administration of progestin through a levonorgestrel-releasing intrauterine device is a good alternative as the progestin part of continuous combined hormone replacement therapy because it effectively opposes the estrogenic effects on the endometrium and induces amenorrhea in most cases.

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 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.

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.

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.