Estrogenic Side Effects Research Articles

Reduction of the estrogenic side effects of the mammary tumor-inhibiting drug [1,2-bis(2,6-dichloro-4-hydroxyphenyl)- ethylenediamine]dichloroplatinum(II) by variation of ring substituents.

[1,2-Bis(4-methoxy/4-hydroxyphenyl)ethylenediamine]dichloroplatinum-(II) complexes with Cl-, CH3-, or OCH3-substituents in the ortho-positions of the aromatic rings (meso-1-PtCl2, D,L-1-PtCl2, meso-2-PtCl2, D,L-2-PtCl2, meso-3-PtCl2, meso-4-PtCl2, meso-5-PtCl2) were tested on the MDA-MB 231 breast cancer cell line, the lymphocytic leukemia P388, and the estrogen receptor-positive and -negative MXT mammary carcinoma of the mouse (MXT,ER(+)-MC, MXT,ER(-)-MC). The comparison of the effects of methoxy-substituted complexes (meso-1-PtCl2, D,L-1-PtCl2, meso-3-PtCl2) with those of the respective hydroxy-substituted ones (meso-2-PtCl2, D,L-2-PtCl2, meso-4-PtCl2) shows that a reduction of estrogenic effects as well as a total loss of the mammary tumor-inhibiting activity takes place on methylation of the 4-OH group. The exchange of the 2,6-standing chlorine atoms by methyl groups in meso-2-PtCl2 led to the non-estrogenic, but on the MXT,ER(+)-MC highly effective derivative meso-4-PtCl2 which proved to be also cytotoxic on ER(-)-tumors such as MXT,ER(-)-MC, and the P388 leukemia.

Contraceptive implants

Available contraceptive implants appeal to women of diverse cultural and socioeconomic background because they offer long-term contraception, safety, effectiveness, reversibility and lack of estrogenic side-effects. Experience with Norplant I indicates that despite some side-effects the continuation rate is the highest for any reversible method of contraception. Disruption of the menstrual cycle is the main reason for discontinuation, hence research effort needs to focus on the mechanism of progestogen-induced endometrial bleeding and appropriate therapy. Implant service programs should have trained and skilled personnel who can provide adequate counseling that complements any public education effort and also provides effective services. Because contraceptive implants offer no protection against sexually transmitted infections, those who engage in high-risk sexual behavior should be encouraged to use condoms as well.

Endometriosis and tamoxifen therapy

Tamoxifen is an estrogen antagonist/agonist often associated with antiestrogenic effects such as hot flushes and vaginal dryness in premenopausal women. Estrogenic side-effects, such as thromboembolic phenomena and endometrial proliferation has been reported in postmenopausal women. Paradoxically, tamoxifen has also been shown to be capable of increasing estrogen levels in premenopausal women. Since tamoxifen is being used more frequently in this group of women, potential adverse effects are only now being recognized. Two cases of premenopausal women who developed symptomatic endometriomas while on tamoxifen for breast cancer, are reported. Stimulation of endometriosis should be considered when pain and an ovarian mass develops in a woman on tamoxifen. The unique effects of tamoxifen in premenopausal women may contribute to this even in the presence of regular ovulation.

Synthesis and evaluation of the anti-mammary tumor activity and of the estrogenic side effects of [1,2-bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamine]platinum(II) complexes

The synthesis and structural characterization of mammary tumor-inhibiting, diastereomeric [1,2-bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamine]platinum(II) complexes with 2,6-Cl 2, 2-F, 6-Cl, 2-Cl, 6-F and 2,6-F 2 substituents ( 1-PtSO 4 to 4-PtSO 4) are described. The related 1,2-diphenylethylenediamines ( 1–4) are synthesized by stereoselective meso-meso and d,l-d,l diaza-Cope-rearrangement reactions and coordinated to platinum(II) with K 2PtI 4 ( 1-PtI 2 to 4-PtI 2). The subsequent reaction with Ag 2SO 4 leads to the respective sulfatoplatinum(II) complexes. They were tested for their anti-tumor activities on the hormone-sensitive and-insensitive MXT mammary carcinoma implanted in mice (MXT-MC, ER + and MXT-MC, ER −). Complexes with F atoms in the neighborhood of the 3-hydroxy group showed strong inhibitory effects on the MXT-MC, ER +. The best effects were found for the diastereomeric 2,6-F 2-substituted complexes, meso- 4-PtSO 4 and d,l- 4-PtSO 4. These complexes are strongly active both on the MXT-MC, ER + and the MXT-MC, ER − and cause no estrogenic side effects.

Benefits and risks of oral contraceptive use.

As a general rule, the lowest-dose oral contraceptive should be prescribed that minimizes side effects while maintaining contraceptive protection. A woman who experiences mild side effects should be encouraged to tolerate symptoms for three menstrual cycles before a decision is made to change the prescription. Compliance may also be improved by informing women of the noncontraceptive health benefits of oral contraceptives: less menstrual blood loss and a lower incidence of menorrhagia, irregular bleeding, benign breast disease, endometrial cancer, dysmenorrhea, ovarian cysts or tumors, and salpingitis. Adequate patient education and supportive counseling are key factors in patient satisfaction and hence compliance.

Potentielle Antiöstrogene vom Typ des 1,2‐Diphenyl‐1‐pyridyl‐but‐1‐ens. Teil 2: Biologische Prüfung

Z-1-(4-hydroxyphenyl)-1-(4-resp. 3-pyridyl)-2-phenyl-but-1-enes Z-1 and Z-2 and their acetates Z-1a and Z-2a are weak estrogens (uterine weight test, immature mouse), which cause a marked tumor growth inhibition on the hormone-dependent MXT mammary carcinoma of the mouse. No or just slight estrogenic side effects determined by uterine weight are detectable in this tumor experiment.

Clinical use of oestrogens and progestogens

Oestrogens cure climacteric complaints and prevent the late sequelae of oestrogen deficiency. Prevention of myocardial infarction and of osteoporosis is now the main argument for long-term substitution of oestrogens and progestogens in the post-menopause and leads to a reduction of overall morbidity and mortality in users. Indications, contraindications, some side effects, risk-benefit and cost-benefit considerations are discussed and practical advice for oestrogen medication with regard to doses, preparations and the addition of progestogens is given.

Adrenocortical Function in Prostatic Cancer Patients: Effects of Orchidectomy or Different Modes of Estrogen Treatment on Basal Steroid Levels and on the Response to Exogenous Adrenocorticotropic Hormone

Basal serum levels and ACTH-induced increments ('delta-values') of dehydroepiandrosterone (DHA) and its sulfate (DHAS), 4-androstene-3,17-dione (A-4), 17 alpha-hydroxyprogesterone (17-OHP), cortisol and testosterone and serum albumin levels were studied in patients with prostatic cancer before treatment and after orchidectomy or during estrogen treatment (intramuscular polyestradiol phosphate during the first 3 months, followed by another 3 months with additional oral ethinyl estradiol). Orchidectomy as well as single drug intramuscular or oral + intramuscular estrogens exerted a similar suppressive effect on basal levels of A-4 and 17-OHP. Orchidectomy caused a slight decrease in basal DHAS, while combined oral + intramuscular estrogens caused a pronounced decrease in basal DHAS and also in DHA. Single drug intramuscular estrogens did not affect basal DHA or DHAS levels. Increased basal cortisol levels appeared during combined oral + intramuscular estrogen therapy. delta DHA and delta A-4 values were unaffected by endocrine treatment, but delta 17-OHP and delta cortisol increased slightly after orchidectomy and during estrogen therapy. Significantly decreased albumin levels were only observed during combined oral + intramuscular estrogen treatment. Determination of estriol, which is a major metabolite of estradiol originating from polyestradiol phosphate, revealed significantly higher estriol levels during combined oral + intramuscular estrogen treatment than during single drug intramuscular estrogen therapy, indicating an increased induction of hepatic 16 alpha-hydroxylase activity. The pronounced decreases in DHAS and also in DHA during combined oral + intramuscular estrogen treatment are probably another reflexion of the liver side effects of oral estrogens.

Late results of complementary specific immunostimulation in metastatic prostate carcinoma.

Calculation of the 5-year actuarial survival reveals a clear superiority of a combination of estrogenic hormone therapy with specific immunostimulation as compared to hormone therapy alone. The aim of this investigation was to show that specific immunostimulation complementary to estrogenic hormone therapy can substantially improve the results of the latter. Because of the appreciable side effects of estrogens, we have abandoned them as basic therapy. Today, we combine specific immunotherapy with RH-LH analogs and androgen receptor blockers and hope to attain further improvement of the actuarial survival in metastatic prostate carcinoma.

Nonsteroidal antiestrogens and partial estrogens with prostatic tumor inhibiting activity.

Antiestrogens and partial estrogens of the stilbene (1 and 4), triphenylbutene (2) and diphenylethane (3) series were tested for their potential prostatic tumor inhibiting activity. Compounds 1 and 2 exerted a strong inhibitory activity on prostate and seminal vesicle weight of intact rats and mice, whereas the strong antiestrogen 3 and compound 4 had no or only a slight effect. The tumor inhibiting activity of 1 and 2 on the hormone-dependent R 3327 Dunning prostatic carcinoma of the rat was strong and comparable to that of castration or administration of the potent estrogen DES. Compounds 1-4 had no direct antiandrogenic effect in castrated, testosterone-substituted rats and mice, and no affinity for the androgen or progesterone receptor. To the estrogen receptor from prostatic tumor cytosol, however, 1-4 had good receptor affinities. As the partial antiestrogen 1 and the partial estrogen 2 have much lower estrogenic properties than DES, but still have strong prostatic tumor inhibiting properties, they may offer a suitable alternative to conventional therapy of prostate carcinoma because of their possibly low estrogenic side effects.

Catechol estrogens of the 1,1,2-triphenylbut-1-ene type: relationship between structure, estradiol receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activities.

1,1,2-Triphenylbut-1-enes (26-35), which are substituted with one or two 3,4-diacetoxy groups or with one 3,4-diacetoxy and one 3- or 4-acetoxy group in two aromatic rings, were synthesized. The occurring E and Z isomers were isolated, and their identity was established by 1H NMR spectroscopy. A study on structure-activity relationship was carried out with regard to estradiol receptor affinity in vitro, estrogenic and antiestrogenic properties in the immature mouse, and inhibition of the hormone-dependent MXT mammary tumor of the mouse in vivo. Among the tested compounds, most of the 1,1-disubstituted 1,1,2-triphenylbut-1-enes (29, Z-30, Z,E-31) and (E)-1-(3-acetoxyphenyl)-1-phenyl-2-(3,4-diacetoxyphenyl)but- 1-ene (E-35) as well as its respective Z isomer (Z-35) exerted antiestrogenic properties. Compounds Z-30, Z,E-31, Z-35, and E-35 inhibited the growth of the hormone-dependent MXT tumor. The best antitumor effect without estrogenic side effects during therapy was shown by E-35.

ChemInform Abstract: 2‐Phenylindenes: Development of a New Mammary Tumor Inhibiting Antiestrogen by Combination of Estrogenic Side Effect Lowering Structural Elements.

AbstractPhenylindene (II) ‐und (III) werden synthetisiert und auf antiöstrogene, Brusttumoren unterdrückende Wirkung untersucht.

Treatment of Advanced Prostatic Carcinoma With D-Trp-6-LH-RH

Twenty patients with stage D2 prostatic carcinoma were treated for up to 18 months with D-Trp-6-LH-RH. Results of more than 3 months of treatment on these 20 patients are reported. The analog was given SC once daily at a dose of 1,000 micrograms/day. All patients had bone pain and high levels of acid and alkaline phosphatase. After the first week of D-Trp-6-LH-RH administration, major decreases in bone pain and reversal of the signs of prostatism were observed. Acid phosphatase gradually fell, achieving normal values after 12 weeks. Initial plasma testosterone was within normal limits, but during treatment with D-Trp-6-LH-RH it fell to castration levels. Resting values of PRL, GH, TSH, and cortisol did not show significant changes. After TRH, TSH increased in five patients, but five did not respond. However, at 2 and 4 months, all patients released TSH in response to TRH. Two patients died during the treatment with D-Trp-6-LH-RH despite initial subjective responses and decreases in testosterone levels. The rise in acid phosphatase levels in these two patients was accompanied by a general deterioration, suggesting that they had androgen-independent cancer. One patient who developed progressive hepatic, bone, and pulmonary metastases in spite of previous orchiectomy was also treated with the analog. Three months later his acid phosphatase levels were within normal values, and partial regression of metastases was observed. These results demonstrate that D-Trp-6-LH-RH and other LH-RH agonists can be used as an effective endocrine therapy for advanced prostate carcinoma, thereby avoiding the side effects of estrogens or the psychological impact of surgical castration.

Photosensitized irreversible binding of estrone to protein via a hydroperoxide intermediate: An explanation of (photo-)allergic side-effects of estrogens

After irradiation (γ>425 nm) for 15 min of a solution of [4- 14C]-estrone, albumin and the photosensitizer hematoporphyrin in phosphate buffer, more than 30% of the radioactivity could not be extracted. When the protein was added after irradiation, irreversible binding also occurred. Sephadex gel filtration showed that the radiolabel was bound to albumin as well as to the photosensitizer. A 10β-hydroperoxide is the reactive intermediate in this binding. Inasmuch as phenolic steroids coupled to proteins have been used for the induction of estrogenic-specific antibodies, the irreversible binding observed between estrone and albumin by photosensitization might be an explanation for (photo)allergic disorders associated with estrogens.

New drug evaluations amiloride (Midamor, Merck, Sharp and Dohme).

Amiloride is a potassium-sparing diuretic that is pharmacologically similar to triamterene. It has been widely used abroad for several years, alone and in combination with hydrochlorothiazide. As a potassium-sparing agent, amiloride appears to be approximately as effective as triamterene and spironolactone and to have a longer duration of action than triamterene, allowing once daily dosing. The diuretic effect of amiloride is mild, as are all agents that act at distal tubular sites. Amiloride appears to have an antihypertensive effect approximating that of the thiazides and spironolactone-an advantage over triamterene, which is devoid of antihypertensive effects. Amiloride will probably be most useful as a potassium-sparing agent in combination with the thiazide and loop diuretics. It should be kept in mind, however, that many patients on thiazide diuretics do not need supplemental potassium or potassium-sparing agents if they have no other complicating factors, such as digitalis therapy. When hypokalemia causes symptoms, a potassium-sparing agent have advantages over oral potassium supplements in patient tolerance and compliance. Because of the possibility of tumorigenicity and estrogenic side effects, spironolactone's popularity has been decreasing in recent years. Amiloride will probably be a strong competitor of triamterene and spironolactone because of its longer duration of action than triamterene and, from early indications (cf. ticrynafen), more benign side effects than spironolactone. The drug should be used with great caution, if at all, in patients with impaired renal function, however. The benefits of amiloride will have to be weighed against the cost of the drug in individual patients.

Side effects of estrogens

Side effects of estrogens

ChemInform Abstract: HYPOLIPIDEMIC ACTIVITY OF PHTHALIMIDE DERIVATIVES. 1. N‐SUBSTITUTED PHTHALIMIDE DERIVATIVES

AbstractDie Phthalimide (I) werden nach der Gabriel‐Reaktion oder aus Phthalsäureanhydrid und Aminen mit anschließendem Ringschluß dargestellt.

Hypolipidemic activity of phthalimide derivatives. 1. N-Substituted phthalimide derivatives.

The general lipid-lowering action of the N-substituted phthalimide derivatives reported herein, as well as the activity of potassium phthalimide, implicates the phthalimide moiety as possessing hypolipidemic activity in rodents. Compounds containing substituents with chain lengths of four carbon or oxygen atoms showed the best hypolipidemic activity in the series tested. Tests involving 1-N-phthalimidobutan-3-one demonstrated a dose-dependent hypolipidemic action free of estrogenic side effects, with no apparent deposition of cholesterol in body organs, and with a high therapeutic index. Further work on the hypolipidemic activity of phthalimido, as well as other imido compounds, is underway.

Experience with medroxyprogesterone acetate (Depo-Provera) as an injectable contraceptive.

Depo-Provera injections appear to be a safe and effective alternative for women who cannot tolerate the estrogenic side effects associated with oral contraceptives or the pain and bleeding associated with IUDs. However, women considering the method should be fully aware of the possible risks: (a) inability to withdraw the drug promptly in the event of a serious reaction, (b) disruption of menstrual patterns, and (c) delayed return of fertility after discontinuing therapy. Some women may consider the required trip to the doctor every 3 months an additional disadvantage. For women in developing countries where anemia and nutritional problems are prevalent, Depo-Provera has additional advantages in relation to IUDs and OCs: it causes less bleeding than IUDs or OCs and, unlike oral contraceptives, it does not suppress vitamin levels (4-8). Since it requires a trip to the doctor every 3 months, it also provides a better opportunity for medical supervision and care. For postpartum women who which to breastfeed their babies, Depo-Provera has the additional advantage of causing no adverse effect on lactation (1, 2, 13, 14, 16, 18, 19, 25, 32, 36).

Daily chlormadinone acetate as an oral contraceptive

Two-hundred and sixty-seven patients took chlormadinone acetate, 0.5 mg daily, for a total of 3,199 months. The overall pregnancy rate and the rate for method failure were 4.5 and 3.7 pregnancies/100 women years, respectively, as calculated by the Pearl formula. Similar results were obtained using the life-table method. The main advantage of this oral contraceptive was its lack of estrogenic side effects. The major disadvantages were the relatively high pregnancy rate and the high incidence of abnormal bleeding among its users.