[Endometrial hyperplasia and its relation to hormone therapy].
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Ovulation inhibition by the monophasic oral contraceptive containing 75 ug of gestodene and 30 ug of ethinyl estradiol was evaluated in 25 healthy volunteers for five cycles: a pretreatment cycle, three treatment cycles, and a posttreatment cycle. Serum luteinizing and follicle- stimulating hormones, estradiol, and progesterone levels were measured on days 8 through 17; progesterone was measured once, around day 21. Pelvic ultrasound examinations were performed on cycle days 8 to 17, luteinizing and follicle-stimulating hormone levels reached values on the lower limit of detection. Luteal activity was not detected in treated cycles. Follicular activity, which was reflected by estradiol levels, was mot strongly depressed during the first treated cycle. Pelvic ultrasound examinations confirmed excellent inhibition of follicular maturation. Restoration of ovarian function in the posttreatment cycle was excellent and showed a midcycle hormonal profile identical to the pretrial cycle.
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Depo-medroxyprogesterone acetate (DMPA) in the conventional dose of 150 mg, was administered intramuscularly to 49 healthy, already sterilized, Thai women on cycle day 5 (13 subjects), day 7 (12 subjects), day 9 (13 subjects) and day 11 (11 subjects) of normal menstrual cycles. Serum progesterone levels were then monitored in order to ascertain the latest follicular phase day in the cycle (up to day 11) when ovulation would be inhibited in the first month after injection. Among the 25 subjects who received DMPA on day 5 and 7, no longitudinal serum progesterone level rises indicative of ovulation were detected. When DMPA was given on day 9 and 11, 2 out of 13 subjects (15.39%) and 3 out of 11 subjects (27.28%), respectively, had serum progesterone levels characteristic of ovulation. It is concluded that the initial cycle's ovulation can also be inhibited when DMPA is administered on day 7 of that cycle. However, DMPA administered on day 9 and 11 failed to inhibit ovulation of that cycle in some of the subjects.
Recent studies suggest that the antiprogestin RU486 may have a direct effect on human ovarian luteal function. To further examine this possibility, we have studied the effect of RU486 on ovarian steroidogenesis using human granulosa cells obtained from women undergoing in vitro fertilization. RU486 at concentrations of 0.1, 2, 5, 10 and 100 nM was incubated with 10(5) granulosa cells over 72 hours. Significant suppression of progesterone production occurred following treatment of cultured cells with 2, 5, 10, and 100 nM RU486 at 24 hours (p less than 0.05) and 48 hours (p less than 0.01). At 72 hours, significant decreases in progesterone production were observed with 10 nM (p less than 0.05) and 100 nM RU486 (p less than 0.01). The greatest effect of RU486 on progesterone production occurred at 24 hours of incubation (slope = -8.03) compared with 48 (slope = -4.71) or 72 (slope = -2.31) hours (p less than 0.01). Maximal suppression of progesterone production occurred using 10 nM RU486 with no further significant suppression observed with 100 nM RU486. Other steroids (R5020, DHA) failed to suppress progesterone production suggesting that the observed inhibitory effect on progesterone was specific to RU486. To better understand how RU486 decreases progesterone production in granulosa cell cultures, we measured human ovarian 3B-hydroxysteroid dehydrogenase (3BHSD) in the presence and absence of RU486 in vitro. A significant dose-dependent decrease in the activity of 3BHSD was observed at concentrations of RU486 that were equal to or greater than substrate concentration. Taken together, these findings suggest that RU486 may directly affect human ovarian progesterone production through a mechanism that involves a reduction in 3BHSD activity.
Uterine contractility was recorded on cycle day LH+6 to LH+8 in a control and treatment cycle in 14 healthy non-pregnant volunteers. In the treatment cycle the subjects received either 50 mg of the antiprogestin RU 486 daily for three days or 40 mg of the anti-estrogen tamoxifen daily for two days. The treatment started on day LH+2. During the recording, 2 to 5 micrograms PGF2 alpha was administered into the uterine cavity. The plasma levels of progesterone and estrogen were the same in both the control and treatment cycles. RU 486 caused a significant increase in uterine contractility expressed in Montevideo Units (MU) and a decrease in uterine tonus in comparison with corresponding data obtained in the control cycle. Following treatment with tamoxifen, uterine contractility was lower but the difference was not significant. PGF2 alpha invariably caused a stimulation of uterine contractility. However, treatment with the antihormones did not influence the response. The result of the present study indicates that the change in uterine contractility occurring in the latter part of the menstrual cycle and during menstruation is due to progesterone withdrawal.
I recount my involvement in the development of biologically active, totally synthetic steroid hormones since 1941. The reasons for my approach to the first total synthesis of a potent androgen are given. I touch on the even more important general synthetic outcomes from ideas generated by the search for useful amounts of a cortically active hormone, such as novel angular methylations, partial hydrogenations of aromatic systems (Birch reductions), and novel usages in synthesis based on the unique structures so generated. The Birch process was critical for synthesis of the first oral contraceptives. A need to explain the structures of Birch reduction products and the experimental requirements resulted in further elucidations of the mechanism of reduction processes, notably for aromatic compounds. The first theoretical and practical distinction between structures of products as determined by a reaction rate or an equilibrium position was first exploited experimentally in the deconjugation of cholest-4-en-3-one in the final step of the first facile total synthesis of cholesterol. A knowledge gained of the biosynthesis of steroids and its specific enzymes helped to initiate my general polyketide theory of biosynthesis and also my idea of outdoing enzyme achievements with organometallic complexes ("inorganic enzyme chemistry"). I assert the high historic importance of steroids in promoting the advance of general organic chemistry within many fields.
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BACKGROUND: The occurrence of hepatocellular neoplasms is frequently reported in young females. The role of oral contraceptives in the development of these tumors is considered. METHODS: A 14-cm tumor was diagnosed in a 24-year-old female who had been taking the contraceptive pill for the last 3 years. Numerous blocks of this lesion were histologically and immunohistochemically analyzed. Some fragments of the lesion were snap-frozen in order to search for sex hormonal receptors and hepatitis B and C virus. RESULTS: On histological examination, the tumor was found to be a hepatocellular, multilobular adenoma with small foci of hepatocellular carcinoma. Neither hepatitis B virus nor hepatitis C virus was found in serum or in the tumor. Nuclear estrogen receptors and progesterone receptors were detected by immunohistochemical analysis in both the adenoma and the carcinoma, but only progesterone receptors were detected by a radio-ligand binding assay in the tumor. CONCLUSION: This finding suggests that the contraceptive pill may stimulate the growth of hepatocellular, multilobular adenomas through the binding of hormonal compounds to their specific receptors within tumoral cells.
Hormonal contraception with a combination of a GnRH-agonist (Buserelin) and progesterone was achieved in 47 high risk patients in 547 cycles. In these patients, oral contraceptives were contraindicated because of severe cardiovascular diseases, thromboembolic complications, benign liver tumours, advanced diabetes, terminal kidney insufficiency and severe migraine. Buserelin was administered intranasally in one daily dose of 300-400 micrograms from the 1st day to the 21st day, one dose of 100 mg of Progesterone was given intravaginally daily from the 12th day to the 21st day. Under these conditions, average E2 concentrations were found in the range of 50-60 pg/ml. The discontinuation of progesterone replacement resulted in withdrawal bleeding. Cycle control was acceptable. In 4 cases, this contraceptive regimen had to be discontinued because of side effects or paradox reactions. One patient conceived. In conclusion, GnRH-analogues in a moderate dose can be used to inhibit ovulation without inhibiting follicular maturation and adequate oestrogen production. This costly regimen of contraception requires strict indication and careful monitoring.
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Estradiol and progesterone receptors have been characterized in normal human endometrial biopsy samples. The cytosol and nuclei were prepared from 150-250-mg samples, either processed immediately or kept in liquid nitrogen. The total concentration of estradiol-and progesterone-binding sites (available or occupied with endogenous hormone) were measured in both fractions. Results were best expressed in femto-moles per mg DNA, or in sites per cell, assuming an even distribution of receptor throughout the endometrial samples. The contribution to total binding of non-saturable binding components and of plasma proteins (transcortin or sex steroid-binding protein) was taken into account. Measurements were obtained in more than 300 patients, among whom 54 had completely normal menstrual cycles on the basis of clinical, hormonal, and histological features. Total estradiol and progesterone receptors were highest in the late proliferative phase (about 8,000 and 12,000 sites/cell, respectively) and were very significantly lower in the late secretory phase. During the proliferative phase, estradiol receptors were increased only in the nuclear fraction, whereas progesterone receptors were increased mainly in the cytoplasm. In the early luteal phase, estradiol and progesterone receptors decreased in the cytosol, whereas they remained high in the nuclei. Both receptors were at their lowest level in cytosol and nuclei in the late secretory phase. The changes of total estradiol and progesterone receptor sites and of their respective subcellular distributions seem to depend upon the plasma levels of both hormones and to follow the same cause and effect relationships as those demonstrated experimentally in laboratory animals.
Pseudopregnant rats were treated early in pseudopregnancy with 1 or 10 mg medroxyprogesterone acetate (MPA). Serum FSH, LH and progesterone concentrations were determined on days 2-20 of pseudopregnancy in treated and control rats. The mean duration of pseudopregnancy was 13-5 days in the control animals, but when animals were treated with 1 mg MPA a dioestrous period of 21-4 days was observed. A period with leucocytic vaginal smears of at least 2 months was observed after treatment with 10 mg MPA. Injection with MPA on day 3 of pseudopregnancy did not affect the serum FSH concentrations during the subsequent days. The progesterone pattern was alike in the three groups of animals, i.e. the duration of the activity of the corpora lutea was similar in all groups. However, 10 mg MPA slightly lowered progesterone concentrations on days 4-8 of pseudopregnancy. In the saline-treated rats, LH concentrations decreased from days 2-5, and remained low until they increased after day 11 of pseudopregnancy. This increase was delayed until day 20 in the animals treated with 1 mg MPA, and was not observed in the animals treated with 10 mg MPA. It is argued that the increase of LH concentration at the end of pseudopregnency is not instrumental in the decrease of peripheral progesterone concentration but rather that the decrease in the progesterone concentration leads to the increase in the LH concentration.
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