Dydrogesterone and other progestins in benign breast disease: an overview.

Progestogens appear to have a dual effect on the cell cycle in breast cells and breast cancer cells. There is initially stimulation of mitotic activity. However, continuous application leads to cell apoptosis. This depends on type, dose and length of progestogen application in relation to estrogen action. In benign breast disease the use of progestogens results not only in reduction of mastodynia, but also a reduction in breast gland size and disappearance of nodularity proven by clinical examination and follow-up including breast ultrasound.

Influence of different HRT regimens on mammographic density.

OBJECTIVES: A prospective, randomized, open-label study was conducted to evaluate effects on mammographic density in postmenopausal and late perimenopausal women receiving continuous combined or sequential combined hormone replacement therapy (HRT). METHODS: The subjects were randomized to treatment with low-dose continuous combined HRT containing 1 mg 17beta-estradiol plus 0.5 mg norethisterone acetate (Activelle) or a sequential combined HRT regimen consisting of 0.625 mg conjugated equine estrogens for 28 days plus 5 mg medrogestone for 14 days (Presomen). Mammograms were obtained at baseline and after 9 cycles (each 28 days) of treatment. RESULTS: The majority of women (approximately two-thirds in each treatment group) had no changes in mammographic breast density between baseline and the final study visit. There were no marked differences between treatment groups. Approximately 20% of women in both groups had a slight increase in mammographic density. Only 10-14% of women in both groups had a pronounced increase in mammographic density. The analyses of the degree of change showed no remarkable differences between treatments. CONCLUSION: These results indicate that the increase in mammographic density with a low-dose continuous combined HRT regimen is no greater than that with a sequential combined HRT regimen. The type of progestogen does not have an impact on the extent of mammographic density changes.

Blood flow in the internal carotid and middle cerebral arteries: effects of continuous oral conjugated equine estrogens administration with monthly progestogen supplementation on postmenopausal women.

OBJECTIVE: This study was designed in order to evaluate the effect of conjugated equine estrogens (CEE) on internal carotid and middle cerebral artery blood flow in postmenopausal women. DESIGN: Thirty-four healthy postmenopausal women with intact uteri were randomly divided into two groups of 17 subjects each. The first group was treated for 24 weeks with continuous CEE medication (0.625 mg daily) and cyclical supplementations of 5 mg/day of medrogestone acetate, given on the last 12 days of every 4-week period (Prempak, Wyeth, Italy). The second group received no treatment. The pulsatility indices (PI) of both the internal carotid artery and middle cerebral artery were measured. RESULTS: In the treated group, the PI of the interior carotid artery and MCA was reduced from respectively 0.736 (0.016) and 0.745 (0.009) at baseline, to 0.669 (0.021) and 0.670 (0.011) after 24 weeks (p = 0.01); in the control group, the PI values remained unchanged. The between-group difference for both arteries was significant (p < 0.01). CONCLUSIONS: The administration of CEE with cyclical medrogestone supplementation to postmenopausal women induces a statistically significant reduction in the PI of cerebral arteries.

Effect of hormone replacement therapy for menopause on the mechanical properties of skin.

OBJECTIVE: To evaluate the effect of hormone replacement therapy (HRT) for menopause on the mechanical properties of the skin in healthy women. DESIGN: A group of 114 women, including 43 nonmenopausal controls, 46 menopausal women with HRT and 25 menopausal women without HRT, participated in the study. Mechanical properties of the skin were measured on the volar forearm using a computerized suction device. SETTING: University medical center. Research laboratory in bioengineering and biometrology. RESULTS: Computerized measurements of skin deformability and viscoelasticity revealed differences between the three groups of women. A steep increase in skin extensibility was evidenced during the perimenopause in untreated women. HRT appeared to limit the age-related increase in cutaneous extensibility, thereby exerting a preventive effect on skin slackness. No effect of HRT was found on other parameters of skin viscoelasticity. CONCLUSION: HRT has a beneficial effect on some mechanical properties of skin and thus may slow the progress of intrinsic cutaneous aging.

Effects of progestational agents in treatment of endometrial carcinoma.

Progestational agents induced an objective response in 11.2% of 155 patients with advanced primary or recurrent endometrial carcinoma. Response rates decreased with decreasing tumor differentiation from 40% with Broders grade 1 lesions to 17.5, 2.4, and 0%, respectively, with grades 2, 3, and 4. 17 alpha-Hydroxyprogesterone caproate (Delalutin), 6,17 alpha-dimethyl-6-dehydroprogesterone (Colprone), and 6-methyl-6-dehydroprogesterone acetate (Megace) were the progestogens used; there was no significant advantage for any one agent. Overall, survival after initiation of hormone therapy was 40% at one year, 19% at two years, and 8% at five years. Survival was highly dependent on the degree of tissue differentiation (P less than .001) and was influenced significantly by the estimated tumor volume at the start of therapy (P less than .01) and by the time interval from primary treatment to the beginning of hormone therapy (P less than .01).

Use of progestational agents in endometrial adenocarcinoma.

PIP: Since 1963 there have been 266 patients with cancer of the uterine fundus at the Medical University of South Carolina. Progestational agents were used to treat 54 but 10 received the drugs for less than 1 month. This report relates to the remaining 44. 34 were treated with Depo-Provera (medroxyprogesterone acetate), 9 with Colprone (megestrone acetate), and 1 with Megace (megestrol acetate). Of the 34 patients treated with Depo-Provera 13 showed regression of the tumor; 3 of the 9 treated with Colprone showed regression. In an additional 11 (25%) of cases growth of the tumors was arrested. 7 of these were later found to have abdominal metastases; however, 3 were free of symptoms for over 43 months. A patient on Depo-Provera with lung metastases had recurrence after 62 months when treatment was reduced to every other week but when Colprone was then given, regression again occurred and has continued for almost 10 years. Another patient not responding to Depo-Provera did respond to Colprone. Average duration of regression was 27.7 months, of survival 31.1 months. Arrest of growth was 25 months in some; survival averaged 23.4 months. (The 1 Megace case was in this group.)y Those having progression of tumors lived an average of 9 months with the longest survival 24 months. Of the responders 8 lived from 44 to 111 months and 5 remain alive, 4 now showing no evidence of the cancer. Tumors with well-differentiated, slow-growing lesions were most likely to respond. Site of recurrence did not seem to influence the response. No contraindications were found to use of progestational agents in this type of cancer. Local reactions to the injections were few. Subjective response was frequent even though progression was taking place.^ieng

The effect of medrogestone on plasma lipids and lipoproteins in postmenopausal women using conjugated estrogens: an open randomized comparative study.

OBJECTIVE: To test the hypothesis that the progestogen medrogestone has no effect on changes in lipoprotein metabolism evoked by continuous estrogen replacement therapy, paying special attention to high-density lipoproteins (HDL). DESIGN: Open multicenter randomized comparative trial. PATIENTS: Postmenopausal hysterectomized women aged 49 to 64 years. INTERVENTION: Continuous oral treatment with 0.625 mg daily of conjugated estrogens (CE) alone (n = 55) or CE plus 5 mg of the progestogen medrogestone orally during the last 12 days of each 28-day cycle (n = 59). MAIN OUTCOME MEASURES: At baseline and at cycles 3, 6, and 13 we measured the plasma levels of apolipoprotein (Apo) A1, cholesterol in total HDL and in its subfractions HDL2 and HDL3, using density gradient ultracentrifugation. RESULTS: High-density lipoprotein cholesterol increased from baseline at all assessments in both treatment groups, being significantly greater in the CE group (+15% at cycle 13) than in the CE and medrogestone group (+8%). However, HDL2-cholesterol increased in both treatment groups, but with no significant difference between the two groups. High-density lipoprotein 3 cholesterol increased only in the CE group (+7% at cycle 13); there was no significant change in HDL3-cholesterol in the CE and medrogestone group. Low-density lipoprotein (LDL) cholesterol decreased from baseline at all assessments in both treatment groups (-6% and -9%, respectively, at cycle 13). The change in very low-density (VLDL) lipoprotein cholesterol was not significant in either of the two groups. Medrogestone had no significant effects on the estrogen-induced increases in apo A-1 and triglycerides nor on the decreases in ApoB and LDL-cholesterol. Neither hormone significantly affected VLDL-cholesterol or Lp(a) levels. CONCLUSION: Medrogestone did not eliminate the increase in plasma HDL levels evoked by CE.

Add-back medrogestone does not prevent bone loss in premenopausal women treated with goserelin.

To investigate the effect of medrogestone on bone mineral density (BMD) and bone turnover under conditions of estrogen withdrawal, premenopausal women with endometriosis were treated with goserelin (Zoladex), combined with either placebo (group A, n = 12) or 10 mg medrogestone (Prothil, group B, n = 11) for six months, and followed for an additional six months. Lumbar spine BMD was measured at 0 and 6 month. Markers of bone turnover were serum bone alkaline phosphatase (sBAP) and osteocalcin (sOC) by ELISA, and urinary total pyridinoline (uPYD) and deoxypyridinoline crosslinks (uDPD) by HPLC. Patients in both groups had a similar and significant decrease in BMD after 6 months (4%, p < 0.01). The time course of changes in bone turnover, in contrast, was different in both groups. In group A, crosslink excretion increased from one month onwards, while no changes were seen in group B. In group A, sBAP levels rose during treatment, while in group B, this rise was delayed until treatment was terminated. Additionally, group B showed an initial suppression of sBAP and sOC. In both groups, sOC increased after treatment was discontinued. Medrogestone at 10 mg/d does not prevent lumbar bone loss in premenopausal women under estrogen deprivation. In the medrogestone add back group, the changes in bone turnover are compatible with low turnover bone loss,as ooposed to a state of high turnover seen in the unopposed goserelin group. This effect may be due to glucocorticoid receptor mediated actions of medrogestone on bone.

Comparative effect of short-term topical tretinoin and glycolic acid on mechanical properties of photodamaged facial skin in HRT-treated menopausal women.

BACKGROUND AND OBJECTIVES: Cutaneous intrinsic ageing has been shown to be improved by hormone replacement therapy (HRT). Photoageing is, however, unresponsive to such treatment. The present double-blind study was undertaken to compare the beneficial effect of a 1-month topical treatment with 0.05% all-trans-retinoic acid or 6% glycolic acid. METHOD: Biomechanical properties were measured on facial skin of HRT-treated menopausal women using both topical products on the hemifaces for 1 month. RESULTS: Skin elasticity proved to be significantly higher at the tretinoin-treated site than at the glycolic acid-treated site. CONCLUSION: Objective non-invasive measurements of the biomechanical properties of facial skin show the superiority of retinoic acid over glycolic acid in improving a deleterious effect of ageing.

Sonographic changes in the endometrium of climacteric women during hormonal treatment.

Vaginal sonography of the endometrium is a new method of monitoring the effects of progestogen replacement therapy during the post-menopausal period. The advantages of transvaginal ultrasonic diagnosis are that the uterus can be seen from the fornix vaginae (that is from close range) and that the examination can be carried out whether the bladder is full or not. The differences in the thickness and structure of the endometrium, and the boundary with the surrounding myometrium, enable most of the endometrial changes that occur during the post-menopausal period to be detected sonographically. In the first group of patients we investigated, endometrial carcinoma was detected in 2 out of 60 women suffering from post-menopausal metrorrhagia, the findings subsequently being confirmed histologically. It was observed that post-menopausal women who have regular bleeding during post-menopausal hormone therapy show signs of endometrial proliferation during oestrogen therapy and of secretion during progestogen therapy.

Sensitive skin at menopause; dew point and electrometric properties of the stratum corneum.

OBJECTIVE: A number of menopausal women experience skin sensitive to various environmental threats. METHOD: Two panels of 15 menopausal women on or without HRT were compared. We studied the response of their stratum corneum to variations in environmental humidity, either in air or in response to an emollient. Environment dew point and electrometric measurements on the skin were recorded to search for correlations. RESULTS: Data show that the baseline stratum corneum hydration is influenced by the dew point. HRT improves the barrier function of the skin. The use of emollient further extends the improvement in the functional properties of skin in menopausal women. CONCLUSION: Both HRT and an emollient can counteract in part some of the deleterious effects of cold and dry weather.

Bleeding patterns in peri and postmenopausal women taking a continuous combined regimen of estradiol with norethisterone acetate or a conventional sequential regimen of conjugated equine estrogens with medrogestone.

OBJECTIVES: The aim of this study was to compare the incidence of women presenting irregular bleeding episodes following 9 months of treatment with a low dose continuous combined hormone replacement therapy consisting of estradiol (E(2)) and norethisterone acetate (NETA) versus a sequential hormone replacement therapy consisting of conjugated equine estrogens (CEE) and medrogestone (MG). Secondary aims were to establish the relationship between menopausal age and the occurrence of irregular bleeding for both therapies and to assess the efficacy of both therapies in alleviating menopausal symptoms. METHODS: This was a stratified and randomised, open label study conducted with late peri and postmenopausal women at 35 sites in Austria and Germany. A total of 446 women were randomly allocated into two cohorts based on time since last bleeding and then stratified to either a low dose continuous combined therapy consisting of 1 mg E(2) and 0.5 mg NETA for 28 days or a sequential therapy consisting of 0.625 mg CEE for 28 days and 5 mg MG for the final 14 days. Bleeding and menopausal complaints were continuously assessed. Treatments were administered for 9 lunar months. RESULTS: The incidence rate of women presenting irregular bleeding episodes including spotting during cycle 9 was 12.2% with 1mgE(2)/0.5mgNETA and 25.8% with 0.625mgCEE/5mgMG (P = 0.0014). In the group of postmenopausal women (time since last bleeding > or = 12 months) the incidence of irregular bleeding during cycle 9 was 11.0% for 1mgE(2)/0.5mgNETA and 25.0% for 0.625mgCEE/5mgMG). In the group of late perimenopausal women (time since last bleeding 6-11 months) the incidence of irregular bleeding was similar for both treatments at cycle 3, but markedly less in patients with 1mgE(2)/0.5mgNETA at cycle 6 and 9, being significantly different compared to patients with 0.625mgCEE/5mgMG at cycle 6 (P < 0.05). The cumulative rate of amenorrhea (no bleeding or spotting) achieved with 1mgE(2)/0.5mgNETA was 89% for the postmenopausal women and 83.7% for the late perimenopausal women. Both treatments relieved menopausal complaints equally effective. CONCLUSIONS: Regarding the occurrence of irregular bleeding, the low dose continuous combined therapy was superior to the sequential therapy (0.625mgCEE/5mgMG). The low dose continuous combined E(2)/NETA regimen is also suitable for late perimenopausal women since more than 80% of the women had no bleeding or spotting after 9 months of treatment.

Prevention of postmenopausal bone loss by low and conventional doses of calcitriol or conjugated equine estrogen.

OBJECTIVES: Estrogen deficiency is the most common cause of postmenopausal osteoporosis and estrogen replacement is well known to retard postmenopausal bone loss. Calcium supplement alone is generally considered to be insufficient for the prevention of bone loss associated with estrogen deficiency while the role of calcitriol is unclear. In the present study we examined the efficacy different doses of estrogen or calcitriol in the prevention of postmenopausal bone loss in Thais. METHODS: The subjects consisted of 146 Thai women no more than 6 years postmenopausal. The subjects were randomly allocated to receive 750 mg supplemental calcium alone, calcium and conjugated equine estrogen (CEE) at 0.3 or 0.625 mg, calcium and calcitriol at 0.25 or 0.5 microg daily. Those receiving CEE also took 5 mg medrogestone for 12 days each month. BMD at L2-4 and femoral neck were measured at baseline 1 year and 2 years after treatments. Data were expressed as mean +/- S.E. RESULTS: Subjects on supplemental calcium alone had approximately 2.5% decreases in L2-4 (P < 0.05) and femoral BMD (P < 0.01) at 2 years. CEE (0.3 mg) resulted in 3.20 +/- 1.2% increase in vertebral BMD (P < 0.05) while no significant change in BMD was demonstrated at the femoral neck. Likewise, 0.625 mg of CEE induced 5.4 +/- 1.4% increase in vertebral BMD at 2 years (P < 0.001) without change in the femoral BMD. In regard to calcitriol, no significant change in vertebral or femoral BMD was demonstrated with either 0.25 or 0.5 microg calcitriol. CONCLUSION: We concluded that calcitriol is effective in the prevention of early postmenopausal bone loss in Thais. It represents an option for the prevention of osteoporosis in postmenopausal women who are contraindicated for estrogen replacement.

Sequential addition of low dose of medrogestone or medroxyprogesterone acetate to transdermal estradiol: a pilot study on their influence on the endometrium.

We evaluated bleeding pattern and endometrium following the administration of two of the most common types of progestogens used in hormone replacement therapy, medroxyprogesterone acetate (MPA) and medrogestone acetate. Twenty eight patients in spontaneous menopause were randomly allocated to two groups. Group 1 (n = 14) received 5 mg/day of of MPA and group 2 (n = 14) received 5 mg/day of medrogestone: both the progestogens were sequentially added for the last 12 days of a 21-day period of transdermal estradiol administration (50 micrograms per day). A 7-day treatment-free period completed the cycle. The study treatments were administered for 6 cycles. The endomtria were checked for their thickness by transvaginal ultrasound before starting treatment and at 6th treatment cycle (days 6-10 of the estrogen-only phase and during the period between days 8 and 12 of the progestogen addition). Endometrial biopsies were performed before starting treatment only in the patients with a positive progesterone challenge test and in all the patients at the end of the study during the addition of the progestogen. The bleeding pattern was closely monitored. MPA is accompanied by a thick endometrium with full secretory transformation in all cases. On the contrary, the same dose of medrogestone induced a consistent decrease of estrogen primed endometrium with only 4 cases of full secretory transformation. Four medrogestone-treated patients dropped out due to unscheduled bleeding. A low dose of medrogestone added to transdermal estradiol induced incomplete transformation of endometrium and oligo-amenorrhea more frequently than MPA, but it increased the chances of irregular bleeding. MPA fully transformed the endometrium: periods were thus heavier but regular. None of the patients in either group had endometrial hyperplasia.

[Mechanism of action of progestins in the treatment of hormone-dependent breast cancer (author's transl)]. / Sul meccanismo d'azione dei progestinici nella terapia dei tumori mammari ormono - dipendenti

The in vitro interference of some gestagens with the binding of 3H-17-beta-oestradiol to cytosol specific receptors was investigated with a view to elucidating the mechanism of action of progestins in the treatment of human hormone-dependent breast cancer. A decrease (up to 85%) of oestradiol binding capacity was observed with high concentrations of progesterone, clogestone and medrogestone. These findings are in good agreement with those previously obtained by the same progestins in our laboratory on rat uterine estrogen receptors in vitro or in vivo. These results provide the support for the hypothesis that the mode of action of progestins in the therapy of mammary and perhaps uterine carcinomas is to some extent related to the inhibition of oestradiol binding to cytosol specific receptors.

PIP: For the purpose of explaining the mechanism of action of progestins in the treatment of human hormone-dependent breast cancer, interference of some progestins with the binding of radioactive 17beta-estradiol to its specific receptors in a cytosol substrate in vitro was studied. A decrease of up to 85% in the binding capacity of estradiol was observed with high concentrations of progesterone, clogestone, and medrogestone. These findings appear to confirm those obtained by the same authors using the same progestins on rat uterine estrogen receptors in vitro and in vivo, and support the hypothesis that the mechanism of action of progestins in the treatment of breast and possibly uterine cardinoma is to some extent related to the inhibition of estradiol binding to its specific receptors, thereby inhibiting the formation of the estrogen-receptor system which is the cause of cell growth in such tumors. This would also explain the greater frequency of successful treatment when using higher doses of progestins.

[Tibolone]. / La tibolone.

INDIRECT MECHANISM OF ACTION: Tibolone (OD 14) is the precursor of its active principles that are its metabolites: 3 alpha and 3 beta hydroxylated derivatives. In vivo, the latter behave like estrogens. Certain tissues (liver, endometrium) may metabolize the 3 beta ol derivative into the delta 4 isomer with progestagenic and androgenic activity. The metabolism of the product in other tissues such as the breast and brain is unknown. ACTIVITY: At the dose of 2.5 mg/day, the product expresses an estrogen activity equivalent to that observed with classical doses of estrogens in the brain, genito-urinary tract, vascular endothelium and bone. In the brain and muscle, it also has a slightly androgenic effect and in the breast an antiestrogenic effect. ON METABOLIC LEVEL: The product acts like a minor androgen (lowering triglycerides and HDL cholesterol without interfering in the cholesterol cell flow) and it stimulates fibrinolysis. ON CLINICAL LEVEL: Tibolone treats the symptoms of estrogen privation and protects against bone loss, without inducing bleeding or mastodynia. There is a lack of large epidemiological studies on prevention of fracture risks, cardiovascular effects and breast. Tolerance in the population studied was excellent (healthy population). However, tolerance remains to be assessed in particular sub-groups (populations at risk of certains pathologies).

Serum lipoprotein effects of conjugated estrogen and a sequential conjugated estrogen-medrogestone regimen in hysterectomized postmenopausal women.

The progestogen chosen for addition to estrogen replacement is important because some progestins adversely influence the effects of oral estrogens on lipid metabolism. In this double-blind study, 22 estrogen-deficient hysterectomized women were treated initially for six cycles with either 0.625 mg conjugated equine estrogens for 21 days plus a placebo during the last 10 days of each cycle or the same estrogen regimen with 10 days of 5 mg medrogestone per day. Thereafter, the treatments were crossed over for a further six cycles. Levels of lipids, lipoproteins, and apolipoproteins were determined at baseline and the last day of sixth and twelfth treatment cycles. Conjugated equine estrogen monotherapy resulted is significantly increased levels of high-density lipoprotein cholesterol (p less than 0.01); percent high-density lipoprotein cholesterol (p less than 0.001), and high-density lipoprotein2-cholesterol (p less than 0.001), with significantly decreased total cholesterol (p less than 0.01), low density lipoprotein cholesterol, and atherogenic index (p less than 0.001). Medrogestone caused no attenuation of any of these clinically important lipoprotein changes. Therefore from the lipoprotein aspect medrogesterone is a desirable progestogen.

A comparison of oestrogen-progestogen with clonidine in the climacteric syndrome.

Twenty-three cases of the climacteric syndrome were analysed in a double-blind study comparing the effect of conjugated equine oestrogen (Premarin) and medrogestone (Colpro) with clonidine (Dixarit) on various clinical parameters. The treatment lasted 20 weeks. Statistical analysis of the results indictaed that opposed oestrogen therapy was effective in reducing hot flushes (P < 0,05) whereas clonidine was not. The other variables tested did not attain statistical significance.

[Comparison of the results of radio gold therapy, cobalt 60 teletherapy and chemotherapy in 330 ovarian neoplasms]. / Vergleich der Therapieergebnisse mit Radiogold, Kobalt-6-Teletherapie und Chemotherapie bei 330 Ovarialkarzinomen

From 1960 to 1972, 276 out of 330 cases of ovarian cancer were treated by different techniques of postoperative radiation therapy; 54 advanced cases underwent prospective chemotherapy. Radiogold intraabdominally administered (190 to 300 mCi), telecobalt (5000 rd) or the combination of radiogold and telecobalt was chosen for postoperative radiation therapy. Cyclophosphamide (Endoxan), prednisolone, and gestagenes (Prothil) were given as a long-term chemotherapy. The most successful technique of radiation therapy is confronted with long-term chemotherapy after three years (five years) of survival: Stage I a, b, c: Radiogold = 91.7% (66.7%), chemotherapy (only I c) = 100%. Stage II a, b: Radiogold + telecobalt = 47% (35%), chemotherapy = 85%. Stage III: Radiogold + telecobalt = 25% (0%), chemotherapy = 52%. Stage IV: Radiotherapy = 0%, chemotherapy = 25%. The absolute five-year survival without chemotherapy amounted to 23%. The mortality curve under chemotherapy shows a four-year survival rate of 88%, if tumor cells had been detected microscopically (ascites, omentum), but of only 30% after macroscopical verification of the tumor. Therefore, the maximally possible partial resection of the tumor is recommended in inoperable stages before the beginning of chemotherapy. "Prophylactic" long-term chemotherapy following macroscopically complete surgical treatment is recommended, whenever microscopical spread of tumor cells appears to be possible. In inoperable stages, chemotherapy ought to be applied prior to radiation therapy. In stages I a, b, c, and II a, postoperative irradiation with radiogold (100 mCi) and in stage II b additionally radiation teletherapy of the pelvis (6000 rd) is recommended.