The pharmacokinetics of progesterone after oral administration were investigated. After a single dose of 100 mg, serum concentrations of progesterone around 50-60 nM and of 20 alpha-hydroxy-4-pregnene-3-one around 5-6 nM were recorded within 1-4 hours and elevated levels persisted for 8-12 hours. There were only minor changes in 17 alpha-hydroxyprogesterone concentrations and serum levels of androstenedione and cortisol were unaffected. A significant conversion of circulating progesterone into deoxy-corticosterone was demonstrated. During clinical treatment with oral progesterone the individual serum concentrations of this potent mineralocorticoid were closely correlated to the progesterone concentrations. This observation could be important as regards the etiology of certain clinical disorders characterized by fluid retention. According to competitive binding analyses there was no evidence that progesterone or medroxyprogesterone acetate could cause significant displacement of cortisol from corticosteroid-binding globulin during clinical treatment. The effects of natural and synthetic hormones upon subfractions of high density lipoprotein (HDL) cholesterol and liver proteins were followed in postmenopausal women during replacement therapy with various estrogen-progestogen combinations. The total serum cholesterol level was significantly reduced during treatment with all estrogen regimens. The concentrations of HDL cholesterol, HDL2 cholesterol, apolipoprotein A I and A II were increased in a dose-dependent pattern during unopposed estrogen therapy. The potency of 10 micrograms of ethinyl estradiol was estimated to be equivalent to 3-4 mg of estradiol valerate. Estrogen effects were significantly reversed by levonorgestrel 250 micrograms and also by medroxyprogesterone acetate 10 mg. During treatment with natural progesterone, no changes were recorded in HDL cholesterol or its subfractions. As compared with the lipoproteins, pregnancy zone protein and sex hormone binding globulin (SHBG) were found to be more sensitive to the alkylated than to the non-alkylated estrogen. Both levonorgestrel and medroxyprogesterone acetate clearly reduced SHBG levels after 3 months, whereas micronized progesterone had no such effect. While tamoxifen counteracted the therapeutic and metabolic effects of estrogen the sequential addition of estriol had no apparent influence. Unopposed estrogen treatment enhanced liver lecithin synthesis along pathway I, i.e. reduced the amount of stearic acid and increased the amount of palmitic acid. The effects were dose-dependent and no qualitative differences between ethinyl estradiol and estradiol valerate were recorded.
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Holtorf Medical Group, Inc., Torrance, CA, 90505, USA. kholtorf@cox.net.
Background: The use of bioidentical hormones, including progesterone, estradiol, and estriol, in hormone replacement therapy (HRT) has sparked intense debate. Of special concern is their relative safety compared with traditional synthetic and animal-derived versions, such as conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), and other synthetic progestins. Proponents for bioidentical hormones claim that they are safer than comparable synthetic and nonhuman versions of HRT. Yet according to the US Food and Drug Administration and The Endocrine Society, there is little or no evidence to support claims that bioidentical hormones are safer or more effective. Objective: This paper aimed to evaluate the evidence comparing bioidentical hormones, including progesterone, estradiol, and estriol, with the commonly used nonbioidentical versions of HRT for clinical efficacy, physiologic actions on breast tissue, and risks for breast cancer and cardiovascular disease. Methods: Published papers were identified from PubMed/MEDLINE, Google Scholar, and Cochrane databases, which included keywords associated with bioidentical hormones, synthetic hormones, and HRT. Papers that compared the effects of bioidentical and synthetic hormones, including clinical outcomes and in vitro results, were selected. Results: Patients report greater satisfaction with HRTs that contain progesterone compared with those that contain a synthetic progestin. Bioidentical hormones have some distinctly different, potentially opposite, physiological effects compared with their synthetic counterparts, which have different chemical structures. Both physiological and clinical data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the increased risk associated with synthetic progestins. Estriol has some unique physiological effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry less risk for breast cancer, although no randomized controlled trials have been documented. Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with progesterone. Conclusion: Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animalderived counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT. Further randomized controlled trials are needed to delineate these differences more clearly.
Vittorio Unfer,
Maria Luisa Casini,
Guido Marelli,
Loredana Costabile,
Sandro Gerli,
Gian Carlo Di Renzo
AGUNCO Obstetrics and Gynecology Centre, via G. Cassiani, Rome 15-00155, Italy. vittorio.unfer@lycos.com
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in woman of reproductive age. Although extensive studies have been performed in past decades to investigate the pathobiological mechanisms underlying the unset of this disease, its etiology remains unknown. Progesterone is a hormone of paramount importance in ovulation, implantation and luteal phase support. Low levels of progesterone have been found in the early luteal phase in PCOS patients. Granulosa cells from polycystic ovaries show an altered progesterone production. Moreover, the lack of cyclical exposure to progesterone may have a role in the development of the gonadotropin and androgen abnormalities found in PCOS patients. Ovulation failure and progesterone deficiency may facilitate the hypothalamic-pituitary abnormalities causing the associated disordered luteinizing hormone secretion in PCOS. Progesterone may be administered to PCOS patients in the following cases: to induce withdrawal bleeding, to suppress secretion of luteinizing hormone, in ovulation induction in clomiphene citrate-resistant patients and in luteal phase support in assisted reproduction. We discuss the pharmacologic characteristics of the different routes of progesterone administration with reference to these diverse indications, the therapeutic objectives and patient compliance.
As life expectancy increases, women are spending more time in the postmenopausal phase of life. Diabetes is one of the most common chronic diseases in the world and its prevalence is increasing. Type 2 diabetes mellitus is more common than type 1 (it accounts for 90% of all cases) and is most frequent in obese individuals over the age of 40 years. In this review, the main problems faced by postmenopausal diabetic women are examined, and hormone replacement therapy (HRT) in this group of women is discussed. HRT appears to decrease the incidence of type 2 diabetes mellitus and to improve glycaemic control; the results vary according to the type of HRT and the route of administration. HRT also improves lipid profiles and transdermal delivery seems to decrease triglyceride levels in particular. There are conflicting data on the effect of HRT on coronary heart disease (CHD); however, it may be beneficial in younger postmenopausal diabetic women. Cardioprotective treatment adjuncts (such as statins or low-dose aspirin) may be advised in diabetic women with CHD risk factors who require HRT. However, their prescription is currently not recommended solely for the possible prevention of cardiovascular disease. HRT may also protect women from osteoporosis in diabetes, especially in type 1 diabetes mellitus. It is recommended that the lowest possible effective dose is used. In postmenopausal diabetic women in whom HRT is not suitable, alternatives such as bisphosphonates may be employed. In these women, vasomotor symptoms can also be improved using drugs such as venlafaxine or gabapentin. Based on current data, we have proposed a regimen that could be used for women with diabetes.
Department of Medical Affairs, Watson Laboratories, Inc., and Department of Pharmaceutics, University of Utah, Salt Lake City, Utah.
Based on the use of estrogen therapy/hormone therapy (ET/HT) in postmenopausal women and the prevalence of hypothyroidism in this population, it is estimated that approximately 5% of all postmenopausal women receive treatment with both ET/HT and thyroid hormone replacement. Hormone therapy generally refers to the combined use of estrogens and progestins, the latter administered on a continuous or intermittent basis. HT is indicated for the treatment of postmenopausal women with intact uteri, whereas ET is used in women who have had hysterectomies. Because of its hepatic first-pass effect, oral estrogen therapy, the most commonly used modality of ET/HT, raises the circulating levels of thyroxine-binding globulin (TBG), thereby increasing the bound fraction and decreasing the free (bioactive) fraction of circulating thyroxine (T(4)). As a consequence, oral ET/HT may increase the T(4) dosage requirements of women being treated for primary hypothyroidism as well as alter the pituitary-thyroid axis in euthyroid women. This paper reviews the potential interaction between ET/HT and thyroid hormone replacement based on the prevalence of their concomitant use, mechanistic aspects of the interaction, and recent clinical studies of the effects of oral ET in euthyroid and hypothyroid women. Other agents known to interact with thyroid hormone replacement, including soy supplements, are also reviewed. Because transdermal ET does not affect TBG levels and would not be expected to alter thyroid function, it may be a preferable modality for postmenopausal women who require concomitant treatment with ET/HT and T(4).
Maturitas. 2000 Feb 15;34 (2):97-108
10714903
Department of Obstetrics and Gynecology, The University of Toronto, Ont., Canada. r.casper@utoronto.ca
This review outlines the basic principles of a novel interrupted progestin HRT regimen in which estrogen is administered continuously, and progestin is given in a 3-days on, 3-days off pulsed fashion. The rationale for this regimen is to prevent receptor down-regulation and allow increased estrogen and progestin sensitivity during the progestin-free periods. Background information is provided including the reasons for poor patient acceptance of HRT, and the concerns of the potential association of HRT with breast and endometrial cancer. Experimental studies in the rat are described which provide evidence in support of the rationale for the interrupted progestin regimen. Clinically, two pilot studies examining symptom control, bleeding rates and safety of the interrupted progestin regimen, as well as preliminary results of a third study examining the usefulness of this regimen for addback therapy in GnRH agonist treated patients, are outlined. The preliminary results of phase III trials are presented. These clinical studies all demonstrated good symptom control, low bleeding rates, endometrial protection, and excellent patient acceptance. The combination of continuous estrogen with interrupted progestin appears to result in increased sensitivity to estrogen and progestin in estrogen responsive tissues. As a result, lower doses of estrogen and progestin may be used for HRT with good biological effects. Further clinical studies, preferably in prospective randomized trials, are required to demonstrate an advantage of this new regimen compared to continuous combined HRT.
Department of Obstetrics and Gynecology Piero Fioretti, University of Pisa, Italy.
Body weight was measured, and body fat distribution was determined by dual energy x-ray in early postmenopausal women given either oral calcium (500 mg/day; control group; n = 12) or hormonal replacement therapy (HRT), a combination of estradiol valerate (2 mg/day for 21 days) with cyproterone acetate (1 mg/day in the last 10 days of the treatment cycle; n = 15). There were no differences in basal body weight or body fat distribution in the two groups before the study. In the control group, a significant (P < 0.05) increase in body weight (from 63.6 +/- 2.2 to 65.2 +/- 1.9 kg [corrected] after 12 months) paralleled a slight, but significant (P < 0.05), increase in total body fat mass (from 23.8 +/- 2.2 to 24.7 +/- 2.2 kg), with an increase in fat in the trunk (from 10.2 +/- 0.4 to 11.3 +/- 0.4 kg; P < 0.01) and arms (from 2.4 +/- 0.5 to 2.7 +/- 0.2 kg; P < 0.05). These findings demonstrate a shift to a prevalent central android fat distribution after 12 months of observation in untreated postmenopausal women. Conversely, in the HRT group, total body bone mineral showed a significant (from 1089 +/- 28 to 1106 +/- 29 mg/cm2; P < 0.05) increase after 12 months, with no significant increase in body weight (from 62.2 +/- 1.6 to 62.7 +/- 1.6 kg), and no modifications in trunk (from 10.0 +/- 0.2 to 9.8 +/- 0.3 kg) and arm (from 2.43 +/- 0.2 to 2.5 +/- 0.1 kg) fat, but a significant increase in leg fat (from 7.1 +/- 0.3 to 8.3 +/- 0.4 kg; P < 0.05). The present results suggest that HRT can counteract at least in part the postmenopausal increase in body weight and body fat and prevent central body fat distribution after menopause.
Department of Obstetrics and Gynecology, University of Bari, Italy.
A 11.20-mg dose of progesterone was administered by nasal spray to five healthy fertile women in the follicular phase of the menstrual cycle. Serial blood samples were collected and Cmax (the maximum progesterone concentration reached), Tmax (the time at which Cmax was reached) and the area under the curve (AUC), with the time limits of 0 and 720 min, were calculated. Serum progesterone levels were assayed by means of a non-extraction [125I]radioimmunoassay. The mean Cmax was 4.50 +/- 2.31 ng/ml at a Tmax of 30 min; levels returned to baseline after 720 min. The mean AUC value was 1180.50 +/- 613.90 ng.h/ml. The progesterone administered by nasal spray in fertile women was effective in reaching physiological progesterone levels. Even if a nasal first-pass metabolic effect is taken into account, this route allows progesterone to avoid liver first-pass metabolism and its metabolic consequences.
Department of Obstetrics and Gynecology Piero Fioretti, University of Pisa, Italy.
Postmenopausal women were randomly given either oral calcium (500 mg/day, control group, n = 12) or a combination of estradiol valerate (EV, 2 mg/day for 21 days) with cyproterone acetate (CPA, 1 mg/day in the last 10 days of the treatment cycle, n = 19). EV+CPA reduced (P < 0.01) postmenopausal complaints, inducing regular withdrawal bleeds, with no hysteroscopic or hystologic evidence of endometrial hyperstimulation after 12 months of treatment. In the control group, spine bone mineral density (BMD) and the total body bone mineral (TBBM) decreased (P < 0.01), whereas urinary hydroxyproline excretion (OH-P/Cr), plasma bone Gla Protein (BGP) and lipid profile did not show any significant modification throughout the study. In the EV+CPA group, urinary OHP/Cr and plasma BGP levels decreased (P < 0.01) after 6 and 12 months, whereas both BMD and TBBM showed a small but significant (P < 0.01) increase. In this group, LDL cholesterol significantly (P < 0.01) decreased and HDL levels significantly (P < 0.01) increased after 6 and 12 months. In conclusion, the EV+CPA combination is effective in relieving menopausal symptoms, produces a good cycle control and a favourable lipid profile, preventing postmenopausal bone resorption.
Department of Obstetrics and Gynecology, Medical School, University of Bari, Italy.
11 mg natural progesterone (P) was administered to 20 healthy menopausal women by means of a nasal spray or intramuscular injection. Circulating P levels were calculated at various times after administration. The spray formulation yielded a CMax of 3.75 ng/ml at TMax = 60 min, the area under the curve (AUC)0-720 being 1,481.6 +/- 343. Intramuscular administration yielded a mean CMax of 4.137 ng/ml at TMax = 240 min, the AUC0-720 being 2,491.2 +/- 540. P absorption was faster through the nasal than through the intramuscular route, but intramuscular administration led to high serum levels for a much longer period.
Department of Gynaecology and Obstetrics, Hospital Clinic i Provincial, School of Medicine, University of Barcelona, Spain.
The aim of this study was to determine the effects on plasma lipids and lipoproteins of oophorectomy and various hormone replacement therapy (HRT) delivery systems using low doses of medroxyprogesterone acetate (MPA, 2.5 mg/day). A total of 90 women completed the 1-year follow-up period. Patients were randomly assigned to five groups. The first (n = 16) received 0.625 mg/day conjugated equine oestrogens (CEE) cyclically, the second (n = 20) 50 micrograms/day transdermal oestradiol cyclically and the third (n = 15) 0.625 mg/day CEE continuously. These three groups also received 2.5 mg MPA sequentially for the last 12 days of HRT administration. The fourth group (n = 20) received 0.625 mg/day CEE and 2.5 mg/day MPA continuously, while the fifth (n = 19) constituted a treatment-free control group. After oophorectomy patients showed increases in low-density lipoprotein (LDL), apolipoprotein B and the atherogenic index, whereas after HRT patients exhibited falls in plasma LDL, apolipoprotein B and the atherogenic index and increases in high-density lipoprotein (HDL) and apolipoprotein A1. No significant changes in total cholesterol were observed after surgery or treatment and decreased levels of triglycerides were detected only in the transdermal treatment group.
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U B Ottosson,
J E Damber,
M G Damber,
G Selstam,
F Solheim,
T Stigbrand,
R Södergård,
B von Schoultz
Sex hormone binding globulin (SHBG) and pregnancy zone protein (PZP) are two highly oestrogen-inducible serum proteins. SHBG capacity and PZP level were measured in 49 women treated with three different combinations of ethinyloestradiol and norethisterone. SHBG capacity and PZP were measured before and after 6 mth of treatment and both serum factors significantly increased during treatment for all three groups. PZP induction was found to be more sensitive and mainly to reflect the oestrogen component of a combined preparation while SHBG capacity was more sensitive to the modulating effect of the progestogen.
The relative fatty acid composition of serum lecithin was followed in groups of women during postmenopausal replacement therapy. The effects of estradiol valerate and ethinyl estradiol in two different doses, and the modulating influence of various progestogens and antiestrogens were compared. Unopposed estrogen treatment enhanced liver lecithin synthesis along pathway I, i.e. reduced the amount of stearic acid and increased the amount of palmitic acid. The effect was clearly dose-dependent and even the low dose of 10 micrograms of ethinyl estradiol was more potent than 2 mg of estradiol valerate. No qualitative difference between the two estrogens was recorded. The sequential addition of the antiestrogen tamoxifen significantly reduced the influence of ethinyl estradiol. Liver lecithin synthesis along pathway I may be stimulated by all estrogens and not only by 17C-alkylated compounds. The prostaglandin precursors, dihomogammalinolenic and arachidonic acid, showed a seemingly dose-dependent increase during estrogen treatment. The comparatively weaker effects of estradiol valerate on lipid metabolism should make this non-alkylated estrogen the first choice in clinical practice.
The antiestrogenic effects of tamoxifen and estriol were compared in 39 postmenopausal women during estrogen replacement therapy. Subfractions of HDL cholesterol and its apolipoproteins and the serum levels of two estrogen sensitive liver proteins were followed during three cycles of unopposed estrogen therapy with 10 micrograms ethinyl estradiol daily. During the last 10 days of the following three cycles the women received sequential addition of either 10 mg tamoxifen twice daily or 2 mg estriol twice daily. Tamoxifen clearly reduced the estrogen-induced increase of apolipoprotein AI, HDL2 cholesterol and total HDL cholesterol. In comparison the pregnancy zone protein and sex hormone-binding globulin were more sensitive to the estrogenic as well as to the antiestrogenic effect than the lipoproteins. Tamoxifen also counteracted the therapeutic effect on climacteric symptoms and it seems unlikely that this compound may be clinically useful as an alternative to progestogens during estrogen replacement therapy. The sequential addition of estriol had no apparent effects as compared to unopposed estrogen treatment.
Subfractions of high-density lipoprotein cholesterol and its apolipoproteins were followed up in 58 postmenopausal women during three cycles of unopposed estrogen replacement therapy with 2 mg of estradiol valerate daily. During the last 10 days of the following three cycles the women received sequential addition of either 250 micrograms of levonorgestrel, 10 mg of medroxyprogesterone acetate, or 200 mg of natural micronized progesterone. Both progestogens significantly decreased total high-density lipoprotein cholesterol as well as subfraction 2 of high-density lipoprotein. Data suggest that doses and relative biologic activity of 19-norsteroids and 17-hydroxyprogesterone derivatives are more important for their metabolic effects than are qualitative differences. Natural progesterone had no apparent influence on high-density lipoprotein cholesterol or its subfractions and may develop into an attractive alternative to synthetic progestogens.
The effects of ethinyl estradiol and estradiol valerate were compared in 135 postmenopausal women during estrogen replacement therapy. Subfractions of high-density lipoprotein (HDL) cholesterol and its apolipoproteins and the serum levels of 2 estrogen-sensitive liver proteins were followed during 3 cycles of unopposed treatment with either ethinyl estradiol 10 or 30 micrograms or estradiol valerate 2 mg daily. Estrogen therapy induced significant and dose-dependent changes in all serum factors except HDL3 cholesterol. The effects of 10 micrograms of ethinyl estradiol upon the lipoproteins were 1.5-2.5 times greater than those of 2 mg of estradiol valerate. Sex-hormone-binding globulin and the pregnancy zone protein were the most sensitive markers for the estrogenic effect and these 2 liver-derived plasma proteins were also much more sensitive to ethinyl estradiol than to estradiol valerate. Although satisfactory therapeutic effects were achieved with both estrogens, the marked influence of ethinyl estradiol on liver protein synthesis should make estradiol valerate the first choice in clinical replacement therapy.
Effects of progesterone, progestogens, and danazol on the specific cortisol binding in human plasma.
The interaction of medroxyprogesterone acetate (MPA) with cortisol binding to corticosteroid-binding globulin (CBG) was studied with the use of an aqueous two-phase system with polyethylene glycol and dextran for equilibrium partition. Competitive binding analyses were also performed for progesterone (P), levonorgestrel, norethisterone, danazol, and tamoxifen. P and danazol were found to exert cortisol displacing activity, whereas MPA and the other tested compounds had no such effect. The glucocorticoid effects reported for MPA could not be explained by displacement. In general, P serum concentrations are lower than those of cortisol, and most binding sites on CBG are occupied by the glucocorticoid. At high P levels displacement and an increase in free cortisol may occur. Danazol displacement of cortisol is hampered by its pronounced albumin binding. In conclusion, none of the tested compounds should increase free and biologically active cortisol during normal clinical treatment.
Department of Pathology, University Hospital, Umeå, Sweden.
Malignant transformation is reported in less than 2% of benign cystic teratomas. Although all the elements can undergo this transformation, it is most often seen in squamous epithelium. The malignancy of neural elements is probably the least common event, with only one case previously reported. A case of glioblastoma multiform in a benign cystic teratoma is presented. Its neural derivation was supported by an immunohistochemical staining specific for Glial Fibrillary Acidic Protein (GFAP). Despite very conservative surgery without adjuvant therapy, the patient remains alive and symptom free more than 3 years later.
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Hum Reprod. 2009 Oct 19;:
19840988
Department of Woman and Child Health, Division of Obstetrics and Gynecology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
BACKGROUND Menstrual disturbances in female athletes are often explained as a consequence of energy deficiency. Oral contraceptive (OC) treatment may have favorable metabolic effects. We evaluated effects of OCs on diurnal secretions of insulin, insulin-like growth factor binding protein 1 (IGFBP-1), growth hormone (GH) and cortisol in relation to changes in body composition in athletes with menstrual disturbance compared with regularly menstruating athletes and controls. METHODS Age- and BMI-matched groups of endurance athletes with menstrual disturbance (OAM, n = 9) and regularly cycling athletes (RM, n = 8) and sedentary controls (CTRL, n = 8) were examined, and hormone levels measured, before and after 8 months of treatment with a low-dose combined OC (30 microg ethinyl estradiol + 150 microg levonorgestrel). RESULTS Before OC treatment, the diurnal profile of insulin was lower (P < 0.01) and levels of IGFBP-1 (P < 0.05) and cortisol (P < 0.05) were higher in OAM athletes than in CTRL, whereas GH secretion was higher than in RM athletes (P < 0.05). After treatment, diurnal secretions of these hormones were similar between groups with an increase of IGFBP-1 in the regularly menstruating subjects only (P < 0.001). OC treatment increased body fat mass in OAM athletes (P < 0.01 versus baseline). The change in total fat mass correlated positively with pretreatment diurnal levels of GH (r(s)= 0.67, P < 0.01) and cortisol (r(s)= 0.64, P < 0.01). CONCLUSIONS OC treatment in endurance athletes with menstrual disturbance increases body fat mass and results in diurnal levels of insulin, IGFBP-1, GH and cortisol that are comparable to those in regularly menstruating subjects. These results suggest that OCs improve metabolic balance in OAM athletes.
Department of Obstetrics and Gynecology, Firat University Medical School, Elazig, Turkey.
OBJECTIVE: To compare the effects of raloxifene, estradiol valerate plus dienogest, and soy isoflavones (genistein) on serum concentrations of high-sensitive C-reactive protein in healthy postmenopausal women. METHODS: The 80 healthy postmenopausal women enrolled in the study were randomly allocated to receive 60 mg of raloxifene, 2 mg of estradiol valerate plus dienogest, 40 mg of genistein, or placebo (n=20 in each group). Blood samples were collected at the start of the study and at 3 and 6 months. Lipid profile was also determined. RESULTS: Only the group receiving estradiol valerate plus dienogest showed an increase in serum levels of high-sensitive C-reactive protein compared with baseline values and values in the control and other groups. All 3 treatments resulted in an increase in high-density lipoprotein cholesterol levels and a decrease in total, low-density, and very-low-density lipoprotein cholesterol levels. CONCLUSIONS: Estradiol valerate plus dienogest, but not raloxifene and genistein, increase serum high-sensitive C-reactive protein levels. All 3 treatments, however, have an estrogen-like effect on serum lipid profile.
Jyoti Kalbag,
Cheryl Elder,
Graham Scott,
Yibin Wang,
Slavica Milosavljev,
Philipp Leese,
Jacque Caldwell,
Christiane Rordorf
Department of Exploratory Clinical Development, Novartis Pharma AG, WSJ 210-313, CH-4002, Basel, Switzerland.
This study evaluated the effect of lumiracoxib on the pharmacokinetics and pharmacodynamics of ethinyl estradiol (EE) and levonorgestrel (LN) in Triphasil(R)-28 (a triphasic oral contraceptive). Females stabilized on Triphasil(R)-28 continued on Triphasil(R)-28 alone for another month (Treatment Period 1), then also received lumiracoxib (400 mg daily) or placebo for 28 days each (Periods 2 and 3) in a double-blind crossover design. Plasma pharmacokinetic profiles were assessed on Day 21 of Periods 2 and 3. Progesterone and plasma sex hormone binding globulin (SHBG) concentrations were measured before and 2 hours after Triphasil(R)-28 administration on Day 21 of all three treatment periods. Lumiracoxib had no significant effect on EE or LN pharmacokinetics or on progesterone or SHBG concentrations, indicating that anovulation and Triphasil(R)-28 effectiveness was maintained. Adverse events were similar for lumiracoxib and placebo. Therefore, no clinically important consequences are anticipated if lumiracoxib is coadministered with oral contraceptives containing EE or LN.
Climacteric. 2002 Dec ;5 (4):357-65
12626215
Cit:1
Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm and Department of Obstetrics and Gynecology and Clinical Research Center, Karolinska Institutet, Stockholm, Sweden.
OBJECTIVE: To evaluate the effect of adding testosterone undecanoate 40 mg daily to estrogen replacement on sexual function, psychological well-being and self-esteem in surgically postmenopausal women. METHODS: A letter of invitation to participate in the study was mailed to women who had undergone hysterectomy and bilateral oophorectomy for benign disorders during 1990-98. Fifty women, 45-60 years old, were consecutively recruited and randomly assigned to oral treatment with testosterone undecanoate 40 mg plus estradiol valerate 2 mg daily or placebo plus estradiol valerate 2 mg daily for 24 weeks. A double-blind design was chosen, with cross-over to the other regimen for another 24 weeks of treatment. Forty-four women completed the study. Outcome included scores on McCoy's sex scale questionnaire, the Psychological General Well-Being index and a self-esteem questionnaire, at baseline and after 24 weeks of either treatment. Serum concentrations of total testosterone, sex hormone binding globulin, free testosterone, dihydrotestosterone, androstenedione, estradiol, follicle stimulating hormone and luteinizing hormone were analyzed at baseline and after 24 weeks of both treatment regimens. RESULTS: After 24 weeks, both treatment regimens had significantly improved some of the sexual variables. The addition of testosterone had a significantly better effect on the sex variables 'enjoyment of sex','satisfaction with frequency of sexual activity' and 'interest in sex'. The total McCoy score was significantly increased by both treatments, but there was a stronger effect when testosterone was also given. Although both regimens improved psychological well-being and self-esteem, we found no significant differences between testosterone-estrogen or estrogen alone at 24 weeks. Serum levels of all androgens, with considerable individual variation, increased significantly from baseline after 24 weeks of testosterone-estrogen treatment. Supraphysiological levels were achieved in a significant proportion of the women. Increases in estradiol and sex hormone binding globulin were less marked when testosterone was also given. Both treatments reduced gonadotropin levels. CONCLUSIONS: The addition of testosterone undecanoate improved specific aspects of sexual function more than treatment with estrogen alone. Improvements in well-being and self-esteem were similar for both treatments. If testosterone undecanoate 40 mg daily should be used for clinical treatment, regular monitoring of androgen serum levels is needed.
Department of Obstetrics and Gynecology, J. W. Geothe University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
In a double-blind, controlled, randomized, four-arm, bicentric clinical study, the effect of four oral contraceptives (OCs) on various hormone parameters and serum-binding globulins was investigated. Four groups with 25 volunteers each (18-35 years of age) were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinylestradiol (EE)+ 2 mg dienogest (DNG)(30EE/DNG), 20 microg EE + 2 mg DNG (20EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV)+ 2 mg DNG (EE/EV/DNG) or 20 microg EE + 100 microg levonorgestrel (LNG)(EE/LNG). The study was completed by 91 subjects. Blood samples were taken after at least 12 h of fasting on Day 21-26 of the preceding control cycle and on Day 18-21 of the first, third and sixth treatment cycle. The serum concentrations of free testosterone were significantly decreased by about 40-60% in all four groups, while those of dehydroepiandrosterone sulfate (DHEAS) showed a time-dependent decrease during treatment. Except for EE/EV/DNG, which increased prolactin significantly during the third and sixth cycles, no change was observed with the EE-containing preparations. There was a significant increase in the levels of serum-binding globulins during treatment, which differed according to the composition of the OCs used. The rise in sex hormone-binding globulin (SHBG) was highest during intake of 30EE/DNG (+320%) and lowest with EE/LNG (+80%), while the effect of 20EE/DNG and EE/EV/DNG was similar (+270%). The thyroxine-binding globulin (TBG) levels increased significantly, by 50-60%, during treatment with the DNG-containing formulations, while the effect of EE/LNG was less significant (+30%). The rise in corticosteroid-binding globulin (CBG), which occurred in all groups, was most pronounced in women treated with 30EE/DNG (+90%) and least with EE/EV/DNG (+55%), indicating a strong influence of EE and no effect of the progestogen component. In all treatment groups, the frequency of intracyclic bleeding rose in the first treatment cycle and decreased thereafter. Cycle control was significantly better with 30EE/DNG or EE/LNG than with 20EE/DNG or EE/EV/DNG. There was no significant change in blood pressure, body mass index or pulse rate throughout the study. In conclusion, the DNG-containing OCs caused a higher rise in SHBG and TBG levels than the LNG-containing preparation. The effects on CBG suggest a lesser hepatic effect of 2 mg EV as compared to 20 or 30 microg EE. In contrast to EE, the use of estradiol in OCs appeared to increase prolactin release, while the cycle control was better with the OC containing 30 microg EE.
Department of Obstetrics and Gynecology, University Hospital of Kuopio, Finland.anna_mari.heikkinen@pp.inet.fi
Postmenopausal hormone replacement therapy (HRT) has favorable effects on the serum lipid profile, and it also decreases the risk of cardiovascular diseases. The apolipoprotein E genotype has influence on serum levels of lipids and lipoproteins; apoE allele epsilon4 (apoE4) is associated with high total and LDL cholesterol levels. Genotype also influences the lipid responses to treatment with diet and statins, but the effect of HRT in different apoE genotypes is unknown. We studied the effects of HRT on the concentrations of serum lipids in apoE4-positive early postmenopausal women (genotypes 3/4 and 4/4) compared with apoE4-negative women (genotypes 2/3 and 3/3) in a population-based, prospective 5-year study. In all, 232 early postmenopausal women were randomized into 2 treatment groups: an HRT group (n=116), which received a sequential combination of 2 mg estradiol valerate (E2Val) from day 1 to 21 and 1 mg cyproterone acetate (CPA) from day 12 to 21 (Climen), and a placebo group (n=116), which received 500 mg/d calcium lactate. Serum concentrations of total, LDL, and HDL cholesterol and triglycerides were measured at baseline and after 2 and 5 years of treatment. A total of 154 women completed the final analysis. During the follow-up period, serum total cholesterol and LDL cholesterol concentrations decreased in the HRT group in apoE4-negative women (8.1% and 17.1%, respectively; P<0.001) but did not change in the HRT group in apoE4-positive women or in the placebo group. Serum HDL cholesterol concentrations decreased in the placebo group (apoE4-negative, 3.9%, P=0.015; apoE4-positive, 8.1%, P=0.004) but did not change significantly in the HRT group. Serum triglyceride levels tended to increase in both study groups and genotypes (15.1% to 36.2%, P<0.038 to 0.001), but no differences were observed between the study groups or genotypes, respectively. Our finding was that in postmenopausal Finnish women LDL cholesterol levels in apoE4-negative subjects respond more favorably to HRT than those in apoE4-positive subjects. This finding has potential importance in postmenopausal women with hypercholesterolemia, if confirmed in other studies.
Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Taiwan, R.O.C.
OBJECTIVE: To compare the effects of medroxyprogesterone acetate and micronized progesterone on the lipid profile of postmenopausal women receiving conjugated equine estrogen. STUDY DESIGN: A prospective, clinical study of the changes in lipoprotein profile evaluated in 123 postmenopausal women receiving conjugated estrogen alone (group I), conjugated estrogen combined with medroxyprogesterone acetate (group II) or micronized progesterone (group III) before treatment and six months after. RESULTS: Group I had significantly increased high-density lipoprotein cholesterol (HDL-C) levels (14.4%) after six months as well as decreased low-density lipoprotein cholesterol (LDL-C) concentrations (-6.61%), LDL/HDL and total cholesterol/HDL-C ratios (P <.05). In groups II and III, HDL-C concentrations increased 4.58% and 5.44%, respectively, after six months. LDL-C levels were markedly decreased in group II (8.98%). There was no significant reduction in LDL-C levels in group III. Total cholesterol levels were significantly decreased only in group II (-4.93%). Triglyceride levels were increased with statistical significance only in group III (21.2%, P <.05). LDL/HDL and total cholesterol/ HDL-C ratios were significantly decreased in group II, and this effect was more pronounced in group I. There was no change in the ratios in group III. CONCLUSION: Conjugated estrogen replacement therapy had a persistent cardioprotective effect in postmenopausal women, based on the positive effect on lipoprotein metabolism. Both natural and synthetic progesterones blunt the beneficial effects of estrogen on the lipoprotein profile, and micronized progesterone is not superior to medroxyprogesterone acetate.
Department of Medical Research, Jenapharm GmbH and Co. KG, Jena, Germany.
OBJECTIVE: To compare the effect of two sequential hormone replacement regimens differing in the dose of levonorgestrel on climacteric symptoms, bleeding pattern and lipid metabolism in postmenopausal women. STUDY DESIGN: In a multicentre, randomized, double-blind, active-treatment-controlled study, 210 postmenopausal women were assessed at the end of treatment cycles 3 and 6. The high-levonorgestrel group was treated with 2 mg estradiol valerate (days 1-21) sequentially combined with 0.25 mg levonorgestrel (days 12-21). The low-levonorgestrel group received the same estrogen regimen (2 mg estradiol valerate, days 1-21), but levonorgestrel was administered sequentially in a dose of 0.15 mg during the last 12 days of the cycle (days 10-21). Statistical analysis by Student's t-test for dependent variables (measured values versus baseline) and independent variables (differences between groups), and the composite t-test method for comparison of both regimens with respect to efficacy, was performed. RESULTS: Both groups were statistically comparable. The trial was completed by 137 subjects. Protocol violations occurred in 38 cases. Thirty-five subjects dropped out during the study, 21 of them because of adverse events. Both treatments were equally effective in the treatment of climacteric complaints. There were no clinically significant changes in body weight, blood pressure, haematological tests, and parameters of clinical chemistry. There was a tendency towards a reduction in bleeding intensity in both groups in the second half of the treatment period. The treatment for six cycles with both regimens significantly (P < 0.05) decreased plasma concentrations of triglycerides (significant in the low-levonorgestrel group only), high-density lipoprotein cholesterol, high-density lipoprotein-3-cholesterol, lipoprotein(a) and apolipoprotein A1. In parallel, the serum concentration of total cholesterol increased significantly in both treatment groups, whereas low-density lipoprotein cholesterol increased significantly in the high-levonorgestrel group only. The changes in high-density lipoprotein-2-cholesterol, and apolipoprotein B did not reach statistical significance. CONCLUSIONS: It can be concluded that both sequential combined oral hormone replacement therapy (HRT) regimens were equivalent with respect to efficacy and tolerability in the treatment of women with climacteric complaints. The preparation with the lower dose of progestin showed a tendency towards a less unfavourable influence on the lipid profile.
Department of Obstetrics and Gynecology, University Hospital of Kuopio, Finland.
OBJECTIVE: The positive short-term effects of postmenopausal hormone replacement therapy (HRT) on serum lipids are well known, but it has been suggested that they vanish with time. Cholecalciferol (vitamin D3) is widely used to prevent postmenopausal osteoporosis but the influence of vitamin D3 on serum lipids is poorly known. The long-term effects of HRT and vitamin D3 on the concentrations of serum lipids were studied in a population-based prospective 3-year study. DESIGN AND METHODS: 464 women were randomized into four treatment groups:(i) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate),(ii) Vit D3 (vitamin D3 300 IU/day),(iii) HRT+Vit D3 (both as above),(iv) placebo (calcium lactate 500 mg/day). RESULTS: 320 women completed the study. After three years of treatment, serum concentrations of low density lipoprotein (LDL) cholesterol decreased in the HRT group (10.1%, P<0.001) and the HRT+Vit D3 group (5.9%, P=0.005), increased in the Vit D3 group (4.1%, P=0.035) but remained unchanged in the placebo group. The concentrations of total cholesterol decreased by 5.8% in the HRT group (P<0.001) and by 3.3% in the HRT+Vit D3 group (P=0.023), but did not change in the other two groups. Serum concentrations of high density lipoprotein (HDL) cholesterol decreased in the Vit D3 group (5.2%, P=0.001), HRT+Vit D3 group (3.7%, P=0.046), and the placebo group (4.5%, P=0.006) but did not change significantly in the HRT group. The HDL/LDL ratio increased in the HRT group (10.5%, P=0.006) and decreased in the Vit D3 group (10.5%, P<0.001) whereas no changes occurred in the other two groups. In addition, serum triglycerides increased similarly in all groups (14.0-18.8%, P<0.05-0.001). CONCLUSIONS: Our results confirm the positive long-term effect of HRT with sequential estradiol valerate and cyproterone acetate on serum lipid concentrations. In addition, the results suggest that vitamin D3 supplementation may have unfavorable effects on lipids in postmenopausal women. Pure vitamin D3 treatment was associated with increased serum LDL cholesterol. Furthermore, the beneficial effects of HRT on serum LDL cholesterol content were reduced when estradiol valerate was combined with vitamin D3. However, the relevance of these associations to cardiovascular morbidity remains to be established.
Center for Clinical and Basic Research, Ballerup, Denmark.
The objective of this study was to evaluate the impact of combined estrogen-progestogen therapy on low density lipoprotein (LDL) particle size (determined by the LDL cholesterol/apolipoprotein B ratio). The prospective study was carried out on 139 healthy Danish early postmenopausal women. The subjects were randomized to placebo or to 2 mg estradiol valerate equivalents, either sequentially combined with 75 micrograms levonorgestrel, 10 mg medroxyprogesterone acetate (MPA), or 150 micrograms desogestrel, or continuously combined with 1 mg cyproterone acetate. LDL particle size was calculated before treatment and at nine-well-defined times during the subsequent 84 days. LDL particle size was reduced by all four treatments. This change was statistically significant for estradiol valerate combined with levonorgestrel and MPA (6.2 +/- 2.7% and 5.6 +/- 2.1%(mean +/- SEM), respectively; p < 0.05 for both, placebo-corrected). Estradiol valerate combined with MPA induced cyclic (progestogen-minus estrogen-related values) decreases (-6.3 +/- 2.6%; p < 0.05), and with levonorgestrel there were cyclic increases (5.1 +/- 2.7%; p = 0.067) in LDL particle size (placebo-corrected). In conclusion, combined estrogen-progestogen therapy causes a decrease in LDL particle size. A cyclic variation in LDL cholesterol/apolipoprotein B ratio was observed during sequential treatment.
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