Endometrial disease after treatment with oestrogens and progestogens in the climacteric.

A prospective study of 745 women receiving different regimens of hormone treatment for the climacteric for a total of 21 736 months was performed. There was a lower incidence of endometrial hyperplasia in biopsy specimens in the women receiving cyclical low-dose oestrogen by mouth than in those receiving cyclical high-dose oestrogen by mouth. The incidence of abnormalities in the women receiving sequential oestrogen and progestogen was lower than in either of these two groups. Among the women receiving subcutaneous oestrogen implants the incidence was higher still, but over half of the abnormal specimens were from women who had not taken their progestogen. The incidence of hyperplasia fell with longer courses of progestogen, and no hyperplasia was found in patients taking progestogen for over 10 days each month. The incidence of adenomatous and atypical hyperplasia is significantly reduced by a progestogen when taken for 10 or more days monthly. The absence of vaginal bleeding or of a regular bleeding response does not guarantee histologically normal endometrium in patients taking oestrogens without progestogen.     

Effect of Oral Contraceptives on Glucuronyl Transferase

ORAL contraceptives can cause a wide spectrum of hepatic abnormalities, from mild bromsulphthalein retention to cholestatic jaundice. In the United States it has been estimated that one woman in 10,000 taking oral contraceptives becomes jaundiced¹. This jaundice is cholestatic in type and is similar to intrahepatic cholestasis of pregnancy. Most oral contraceptives are given as combinations of a synthetic oestrogen and progestogen or oestrogen given alone followed by a combination of oestrogen and progestogen. These substances can act on the liver, which plays a central part in their metabolism, to produce a variety of physiological and pathological effects.     

Relations between bleeding pattern,endometrial histology,and oestrogen treatment in menopausal women

Vacuum curettage was performed on 348 women who had received various regimens of oestrogen treatment for an average of 9·7 months for climacteric symptoms. In 62 cases (18%) the specimens were unsatisfactory for histological assessment; among the remainder, however, they showed a normal endometrium in 257 cases (90%), cystic hyperplasia in 21 (7%), adenomatous hyperplasia in 7 (2%), and endometrial adenocarcinoma in one. Cyclical unopposed oral oestrogen treatment (98 cases) was associated with a 12% incidence of endometrial hyperplasia, but among those given an additional five-day course of progestogen in each cycle (37 cases) the incidence was only 8%. No case of hyperplasia occurred among 102 women taking regimens including 10 or 13 days of progestogen. Among women treated with subcutaneous oestradiol implants and monthly five-day courses of oral progestogen (50 cases) there was a 28% incidence of hyperplasia including the one case of carcinoma, though some of those with hyperplasia may not have taken the full course of progestogen. Regular withdrawal bleeding during treatment was associated with a lower incidence of endometrial hyperplasia (6%) than unscheduled breakthrough bleeding (28%), but the one patient with carcinoma had experienced regular bleeding only.The risk of developing endometrial carcinoma from oestrogen treatment may be reduced by avoiding the use of unopposed oestrogen regimens, the addition of more than five days'' treatment with a progestogen, and recognising that a regular bleeding response to oestrogen is no guarantee of a healthy endometrium.     

The effects of oestrogens and progesterone on oestrogen receptors in female rat liver.

The administration of oestradiol-17 beta or ethynyloestradiol as well as the synthetic progestogen norethisterone acetate resulted in translocation of the oestrogen receptor. Progesterone and the synthetic progestogen (+)-norgestrel were ineffective. The increases in nuclear oestrogen receptor content 1 h after injection of each steroid were similar but different subsequently. The increase with oestradiol-17 beta extended for 3--6 h and for at least 9 h with ethynyloestradiol. With norethisterone acetate, nuclear content was still increased after 24 h. Oestrogen injection resulted in cytosol receptor depletion and a 'deficit' in receptor content extending for 6 h, whereas norethisterone acetate-induced translocation was quantitative. With injections of norethisterone acetate + ethynyloestradiol the increase at 1 h and retention of the nuclear receptors were similar to that with norethisterone acetate alone. In contrast, the depletion of cytosol receptor and its restoration were similar to that seen with ethynyloestradiol alone, suggesting that norethisterone acetate did not interfere with the oestrogen receptor replenishment. Specific binding in vitro of [3H]oestradiol-17 beta in liver cytosols was inhibited by (+)-norgestrel and norethisterone acetate, but not progesterone, at concentrations of 10--100 microM. Nuclear receptors present after norethisterone acetate injection bound oestrogen with high affinity (Kd = 1.52 nM), similar to receptors of oestrogen-injected animals. In the uterus, differential retention of nuclear receptors in response to oestrogens is associated with different cellular responses. The differences in the response of the receptor system in liver to the various steroids suggests that the corresponding tissue responses may also be dissimilar. These results are discussed in relation to the problems of liver dysfunction in oral-contraceptive users.     

Randomised comparison of oestrogen versus oestrogen plus progestogen hormone replacement therapy in women with hysterectomy. Medical Research Council's General Practice Research Framework.

OBJECTIVE: To compare the acceptability and symptomatic and metabolic effects of two regimens of hormone replacement therapy in women with hysterectomy. DESIGN: Randomised, double blind comparison. SETTING: Seven group practices in the Medical Research Council''s general practice research framework. SUBJECTS: 321 women with hysterectomy aged 35-59. INTERVENTIONS: Hormone replacement therapy with (a) conjugated equine oestrogen 625 micrograms daily alone or (b) conjugated equine oestrogen 625 micrograms daily plus the progestogen norgestrel 150 micrograms daily for the last 12 days of the ''cycle.'' MAIN OUTCOME MEASURES: Changes in blood pressure, weight, symptoms, and haemostatic and lipid values. RESULTS: After two years 36% (57/158) of women randomly allocated to take oestrogen alone had discontinued treatment as compared with 30% (49/163) of women allocated to take oestrogen plus progestogen. Smokers were more likely to withdraw than non-smokers. There were no clear differences between the two groups in symptoms often attributed to hormone replacement therapy or in blood pressure or weight. At one year low density lipoprotein cholesterol concentrations had fallen substantially in both groups. High density lipoprotein cholesterol concentrations rose to significantly higher values in women taking oestrogen alone compared with those taking oestrogen plus progestogen, though triglyceride concentrations and factor VII activity were also significantly higher in this group. Fibrinogen concentration tended to fall, though not significantly, in both groups, possibly more in women taking oestrogen alone. CONCLUSIONS: Oestrogen plus progestogen was no less well tolerated than oestrogen alone. There was a fairly even balance between possibly beneficial and adverse effects of the two regimens on lipid concentrations and coagulability. Concern that the combined regiment may not have the cardioprotective effects ascribed to oestrogen alone can to some extent be allayed, with reassurance for the growing numbers of women with intact uteri using the combined regiment. Misgivings about the combined regiment in women with hysterectomy on the grounds of its acceptability and its effects on lipid values may also be unfounded.     

Epilepsy and Oral Contraception

A controlled cross-over trial in 20 epileptic women, receiving regular anticonvulsant therapy showed that an oral contraceptive with a low oestrogen/ progestogen content had no significant effect on the average frequency of fits compared with identical dummy tablets.     

Prolonged endometrial stimulation associated with oestradiol implants.

OBJECTIVE--To provide information on endometrial stimulation after discontinuation of treatment with oestradiol implants. DESIGN--Long term follow up of withdrawal bleeding patterns in women taking progestogens cyclically every month after oestradiol implant treatment was ended. SETTING--Specialist menopause clinic. SUBJECTS--10 Postmenopausal patients (at least 12 months'' amenorrhoea after the last spontaneous period) who were treated with oestradiol implants for typical symptoms of oestrogen deficiency. The oestradiol dose was 50 mg, reimplantation occurring roughly every six months. Patients subsequently either needed to discontinue the hormone treatment for medical reasons or expressed a desire to stop treatment. MAIN OUTCOME MEASURE--Duration of endometrial stimulation--defined as the presence of withdrawal bleeding in response to progestogen given cyclically--after insertion of the last oestradiol implant. RESULTS--Four patients eventually stopped bleeding, their mean duration of bleeding being 35 months (range 27-43 months). One patient required hysterectomy 26 months after the last implantation because of persistent irregular bleeding despite treatment with high doses of progestogen. Three patients bled for 22, 30, and 36 months and then restarted oestrogen treatment because symptoms returned. The last two patients subsequently continued to bleed 12 and 21 months after the last implantation. CONCLUSIONS--The duration of endometrial stimulation after implantation can be prolonged, up to 43 months. Insertion of oestradiol implants can carry a long term commitment to the cyclical administration of progestogen and regular withdrawal bleeding if endometrial hyperplasia and carcinoma are to be avoided.     

Chorea and the Oral Contraceptives

The case histories are reported of six women who developed chorea while taking oral contraceptive drugs. The chorea that results from taking compounds containing oestrogen and progestogen has many features in common with chorea gravidarum, and the pathogenesis is probably similar. In some of the patients, however, the sudden onset of symptoms suggests a vascular aetiology.     

Hormone therapy after endometrial cancer

Endometrial carcinoma is listed among the absolute contra-indications to hormone therapy. After all the existing opinions so far, hormone therapy after FIGO stage I or II endometrial cancer is still thought of as a possibility, and up to now the continuous combined oestrogen/progestogen replacement therapy would be recommended. However, until today, only observational studies have been put forward. Although no study has established an increased rate of recurrences or mortality, alternatives such as phytopreparations, tibolone, or, in, particular, psychotherapeutic drugs such as venlafaxine should be considered for the relief of climacteric complaints. Progestogen-only therapy also comes particularly into question. Indeed, the wider discussion about the gestagen effects regarding the risks of breast cancer is to be considered. Generally, after hysterectomy, at least for patients with cardiovascular risk factors, the preference today is to use low-dose oestrogen therapy (patches, gels) instead of continuous combined oestrogen/progestogen replacement therapy, and this also is now recommended for patients after endometrial cancer. This is to be noted because of the risk factors for endometrial carcinomas, such as hypertension, obesity, polycystic ovary syndrome, diabetes mellitus, etc. However, each form of hormone therapy should only be exceptionally recommended, and the patients must be informed about the risks that exist and the use of alternatives.     

Blood pressure and contraceptive use

In a survey of 461 women routinely attending family planning clinics those taking oral contraceptives had significantly higher mean systolic and diastolic blood pressures than those using non-hormonal contraception. There appeared to be a dose-response relation of blood pressure to the progestogen component of two oral contraceptives with an identical 30 μg ethinyloestradiol component. This supports the idea that the progestogen as well as the oestrogen component has an aetiological role in the rise in blood pressure. There was a significant correlation of blood pressure with duration of current use of oral contraceptive but not with total duration of use. There was also a significant negative correlation of blood pressure with time since oral contraceptives were last taken, and women who had stopped using oral contraceptives over a month previously had similar blood pressures to those who had never taken them. In women taking oral contraceptives those who had either a history of hypertension in pregnancy or a family history of hypertension had significantly higher mean blood pressures than those who did not. Both systolic and diastolic blood pressures correlated independently with weight and body mass index, but controlling for the effect of this and age did not affect the above relations. No significant differences in mean blood pressures were found between different ethnic groups, and there was no relation of blood pressure to reported marital state, social class, parity, smoking, or alcohol use.Any oral contraceptive that has a less adverse effect on blood pressure has implications for general prescribing policy; thus even small differences in the progestogen contents of low-dose oestrogen pills may be important.     

Circulating levels of biotin in the fowl (Gallus domesticus): modulation by oestrogen

1. Exogenous oestrogen administration to immature male and female chickens significantly increased plasma biotin and significantly reduced liver biotin concentrations. 2. The elevation in plasma biotin concentrations was dose dependent and maximum values were observed 48 hr after a single injection of oestrogen. 3. A second oestrogen injection significantly increased plasma biotin concentrations compared with values obtained after the initial injection given 10 days previously. 4. Plasma biotin concentrations were significantly increased in female, but not male, birds approaching sexual maturity. This increase coincided with the time of the known surge in endogenous oestrogen production by the developing ovary.     

Assessment of Incremental Dosage Regimen of Combined Oestrogen-Progestogen Oral Contraceptive

Eighty-six women of proved fertility used an incremental dosage regimen of a combined oral contraceptive for a total of 570 cycles over one year. A daily tablet containing 50 μg of ethinyloestradiol and 50 μg D-norgestrel was taken for 11 days and a daily tablet containing 50 μg ethinyloestradiol and 125 μg D-norgestrel for the next 10 days. Withdrawal bleeding occurred during the tabletfree interval of seven days. The new preparation proved to be an efficient contraceptive, well tolerated, and with few side effects. Women who had gained weight while taking other oral contraceptives lost weight when they changed to the new preparation. The regimen allowed a significant reduction in the cycle dose of progestogen, and these results suggest that a further reduction in the cycle dose of both oestrogen and progestogen may be possible without losing contraceptive efficiency.     

Repeatability of events during spontaneous and gonadotrophin-induced oestrus in bitches.

Oestrus induction using equine chorionic gonadotrophin and human chorionic gonadotrophin was successful in five out of six bitches, although the first day of increased plasma progestagen concentration differed considerably between bitches. Induced oestrous periods differed from spontaneous cycles in the timing of vaginal epithelial cell cornification; plasma oestrogen concentrations were generally greater and progestogen concentrations were less in induced cycles. These results suggest that this schedule of oestrus induction would not be suitable for allowing mating on a predetermined day.     

Oestrogen/Progestogen Oral Contraception and Blood Clotting: A Long-term Follow-up

In a long-term study of women taking the combined oestrogen/progestogen oral contraceptives Ortho-Novin and Norinyl-1 the follow-up has been continued for three years and four years respectively.Acceleration of both “intrinsic” and “extrinsic” clotting tests and of specific factor VII and X assays, reported previously at the nine-month stage, persisted throughout the period of study. Acceleration of Chandler''s tube platelet aggregation and hypercoagulable thrombelastographic patterns were recorded. There was, however, no evidence of a cumulative effect after the first nine months.     

The effects of sequential treatment with ethynyloestradiol and medroxyprogesterone acetate on oestrogen and progestogen receptors in breast cancer

As part of a clinical study designed to modulate oestrogen and progestogen receptor (ER and PR) binding site concentrations prior to chemotherapy ER and PR levels have been estimated immediately before treatment, after ethynyloestradiol (EE, 10 micrograms/day, 1 week) and after medroxyprogesterone acetate (MPA, 500 mg/day i.m., 2 weeks) in tumour tissue from 14 women with advanced breast cancer. There was no consistent change after EE treatment. MPA tended to decrease ER and PR levels, though some increases were also seen. Responses (10 complete and 3 partial remissions) to sequential cyclical hormono-chemotherapy were not related to ER or PR levels prior to chemotherapy.     

Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-microgram oestrogen preparations.

Progestogens probably have metabolic effects that may contribute to the increased risk of cardiovascular reactions associated with combined oestrogen-progestogen oral contraceptives. This possibility was investigated by a study of nearly 2000 reports to the Committee on Safety of Medicines from 1964 to 1977. The reports concerned preparations in which norethisterone acetate in doses of 1.0, 2.5, 3.0, or 4.0 mg was combined with 50 microgram of ethinyloestradiol and those in which levonorgestrel in doses of 150 or 250 microgram was combined with 30 microgram of ethinyloestradiol. Observed and expected numbers of reports were compared, using retail pharmacy purchase figures as a measure of the use of different preparations. There was a significant positive association between the dose of norethisterone acetate and deaths from stroke and ischaemic heart disease (IHD); this association was also found for all cases of these two conditions, fatal plus non-fatal. There were no associations of dose of norethisterone acetate with hypertension or venous thrombosis. The higher dose of levonorgestrel was associated with a possible excess of deaths, non-venous plus venous, and an excess of strokes. There was no association between dose of levonorgestrel and hypertension or venous thrombosis. The reports were also used to assess the relative safety of 30-microgram and 50-microgram oestrogen preparations. Those with 30 microgram of oestrogen were associated with significantly fewer reports of death and IHD (both fatal, and fatal plus non-fatal) than those with 50 microgram of oestrogen. In view of the large-scale move towards preparations with progressively lower oestrogen doses, there are no grounds for major changes in oral contraceptive practice. Within the range of preparations currently in use, however, there is a case for minimising the dose of progestogen to reduce the chances of thromboembolism.     

In vivo and in vitro effects of oestradiol-17β on lipid metabolism in Notemigonus crysoleucas

The effects of oestradiol-17β on the gonosornatic index, liver size, hepatic and body lipid levels in the cyprinid teleost, Notemigonus crysoleucas , were investigated. Administration of oestradiol to female TV. crysoleucas during the gonadal preparatory and prespawning seasons stimulates increases in ovarian size. During the early spawning season oestradiol therapy results in a reduction of ovarian gonosomatic index. Oestrogen treatment of males causes a suppression of testicular growth. In female fish exposed to long (15-5L/8-5D) or intermediate (12L/12D) photoperiods oestradiol increases body fat reserves. At short photoperiods (9L/15D) oestrogen treatment of females results in body fat store depletion Low doses deplete and high doses of oestradiol increase body lipid reserves in male fish. The hepatosomic index increases in both male and female fish following oestrogen treatment. Oestradiol therapy during the gonadal preparatory season, but not during the prespawning season, increases total liver lipids. The in vitro effects of oestradiol on liver lipid and carbohydrate metabolism were also examined. Under the conditions used in these experiments, lipid depletion was observed in liver slices incubated with or without oestradiol. Pretreatment of fish with oestradiol before liver tissue was removed drastically reduced in vitro lipid depletion. Oestradiol retards the gluconeogenesis and glycogenesis seen in liver slices incubated in a hormone-free medium.     

In vivo oestrogenicity and binding characteristics of alpha-zearalanol (P-1496) to different classes of oestrogen binding proteins in rat liver

It is now well established that the mycotoxin zearalenone and some of its derivatives possess oestrogenic activity. In the present study, the binding characteristics of [3H]zearalanol (P-1496) to different classes of sites including [1] the oestrogen receptor, [2] the higher capacity lower affinity (HCLA) sites, [3] the antioestrogen sites and [4] a new class of binding sites apparently specific for P-1496 were examined in rat liver. Analysis of the binding by sucrose density gradient centrifugation confirmed that P-1496 binds to the oestrogen receptor but not to the higher capacity lower affinity sites for oestradiol-17 beta. Furthermore, saturation experiments using partially-purified fractions showed that P-1496 binds to the oestrogen receptor with an affinity very similar to that of oestradiol-17 beta (apparent dissociation constants ranged from 0.1-0.3 nM). Competition studies using partially purified cytosolic oestrogen receptor suggested that P-1496 binds to a second high affinity site distinct from the oestrogen receptor. This binding site was further characterized as selective for P-1496 by saturation analysis following the complete occupancy of oestrogen receptor by oestradiol-17 beta. The in vitro binding characteristics of P-1496 were then compared with in vivo effects on concentrations of serum triglycerides. Treatment of ovariectomized female rats daily with 1.5 or 2 mg P-1496/kg body weight resulted in marked increases in the concentrations of serum triglycerides associated with the very low density lipoprotein (VLDL) fraction. Dose-response studies indicated that there was no sex difference with respect to the dose necessary to produce significant increases in serum triglycerides. The present study shows striking similarities between the binding of P-1496 and oestradiol-17 beta to liver oestrogen receptor in vitro. However, differences are observed with respect to their binding to other cytoplasmic components of liver. In addition, although P-1496 is capable of eliciting in vivo oestrogenic effects in liver, it is much less potent than oestradiol-17 beta.     

Venous effects of oral contraceptives

In a five-year analysis of an oral contraceptive trial by the Council for the Investigation of Fertility Control venous effects were the third most troublesome group of side-effects with both combined and sequential therapy. Vein complaints, leg cramps, and thrombophlebitis were significantly more frequent with the combined preparations that contained a relatively low dose of progestogen and a high dose of oestrogen than with the other groups tested. No cases of thrombophlebitis occurred in women taking the strongly oestrogenic sequential groups.Histological examination of uterine curettings showed that most progestogenic combined preparations were associated with a high incidence of dilated endometrial sinusoids, while the oestrogenic sequential regimens and low-dose progestogen-only regimens had a low incidence. The incidence of stromal condensation round the sinusoids correlated with the incidence of leg cramps, and these effects appeared to be specific for each preparation tested.