Low dose aspirin treatment in late pregnancy differentially inhibits cyclo-oxygenase in maternal platelets.

Eighteen pregnant women were treated with aspirin, 37.5 mg once daily by mouth. Treatment was started two weeks before the expected date of delivery, and continued until delivery. Seventeen untreated women were studied concurrently. Platelet thromboxane (TX) production was determined by radioimmunoassay of TXB2 in serum from blood incubated for one hour with thrombin at 37 degrees C. Maternal blood was studied before treatment and at delivery. Fetal blood, from the cord, was studied at delivery. Prostacyclin (PGI2) production by rings of umbilical artery incubated in Hanks' solution at 37 degrees C for one hour was determined by radio-immunoassay of its hydrolysis product, 6-oxo-prostaglandin (PG) F1 alpha. Maternal and fetal blood from untreated women produced similar amounts of TXB2. Aspirin, in the dose regimen used, significantly inhibited TXB2 production in maternal but not in fetal blood, and did not impair PGI2 synthesis by umbilical artery rings. This differential effect on the cyclo-oxygenase of maternal platelets is probably due to the unusual kinetic properties of aspirin, and may prove therapeutically useful.

The effects of subcutaneous hormone implants during climacteric.

Climacteric symptoms in 120 women were treated with a total of 469 hormone implants (oestradiol 50 mg and testosterone 100 mg) over a period of four years. All patients with a uterus were given an oral progestogen to prevent endometrial hyperplasia. There was a marked response to treatment, hot flushes being improved in all patients, depression in 99% and loss of libido in 92%. Patient acceptability of this type of treatment was good and there were few side effects or complications. After therapy, the serum oestradiol exceeded the serum oestrone but remained within normal limits. When climacteric symptoms returned and re-implantation occurred the serum levels of oestrone, oestradiol, luteinising hormone (LH), follicle stimulating hormone (FSH) and testosterone were within the normal range for the reproductive age. This indicates that the return of symptoms is due to a change in the hormone levels rather than absolute hypo- oestrogenism .

Scanning electron microscopy of the endometrial cell surface in postmenopausal women receiving oestrogen therapy.

The surface ultrastructure of normal and abnormal endometrial cells from patients receiving oestrogen therapy for the climacteric syndrome was studied by scanning electron microscopy. Patients with endometrial pathology were treated with oral progestogens. Excessive oestrogen stimulation caused proliferation of cilia and microvilli. Cystic hyperplasia was characterised by a proliferation of cilia until they covered more than one-third of the surface area of the endometrium; further proliferation occurred in cases of adenomatous hyperplasia when the surface was almost completely covered with cilia. Cell morphology remained apparently normal until atypical hyperplasia, when occasional cells appeared large and irregular, or adenocarcinoma occurred, when the surface cells appeared large, pleomorphic and sometimes wrinkled, being mostly devoid of cilia. Although cystic hyperplasia was converted to a normal histological picture of atrophic or pseudo-decidual endometrium by courses of progestogen, the deciliated endometrial cells showed persisting abnormal ultrastructural characteristics.

[Endometrial disease after treatment with oestrogens and progestogens in the climateric (author's transl)]. / Pathologie endometriale apres traitement par estrogenes et progestatifs a la menopause.

PIP: This study was undertaken to examine the frequency of histologic endometrial anomalies with different types of estrogen therapy, whether or not associated to progesterone treatment. 1002 endometrial biopsies were done on 745 women who had received: 1) cyclic treatment with low-dose estrogen; 2) cyclic treatment with high-dose estrogen; 3) sequential estrogen-progestogen treatment; and 4) subcutaneous implant of estradiol. Frequency of abnormalities was 7.0% in the first group, 14.8% in the second group, 1.2% in the third group, and 14.8% in the fourth group. Without drawing definitive conclusions from these results, it seems possible to affirm that the use of progestogen diminishes the risk of endometrial cancer during menopause.^ieng

Hormonal profiles in postmenopausal women after therapy with subcutaneous implants.

Plasma hormones were estimated in 24 postmenopausal patients who had been castrated. Each was given a sub-cutaneous implant of either 100 mg or 50 mg of oestradiol, or 50 mg of oestradiol with 100 mg of testosterone, or 200 mg of testosterone. Plasma hormone estimations were repeated at two weeks, one month and then monthly for up to 12 months. Plasma follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations were seen to fall at two weeks after all implants containing oestradiol. Plasma testosterone concentrations rose from a mean concentration of 1.0 nmol/l to 5.0 nmol/l and 6.7 nmol/l after implants of 100 mg and 200 mg of testosterone respectively. Implants containing oestradiol caused the pretreatment ratio of the concentrations of oestrone to oestradiol to change from 2:1 to 1:2. The implant of 100 mg of oestradiol caused the plasma oestradiol concentration to rise to a mean value of 602.3 pmol/l and those of oestrone to rise to 356.7 pmol/l. The more commonly used implants contain 50 mg of oestradiol and these caused the mean concentration of plasma oestradiol to rise to 346.7 pmol/l and oestrone to rise to 233.9 pmol/l. These values compare favourably with those attained after oral oestrogen therapy.

Oestrogens and endometrial hyperplasia.

PIP: This review of the connection between unopposed estrogen therapy for climacteric symptoms and the development of endometrial hyperplasia briefly outlines the history of the association, and then concentrates on clinical classification problems which muddy the attempts to come to a clear understanding of the relationship between estrogen replacement therapy (ERT) and endometrial cancer. Little agreement exists about the definition of endometrial pathology and of the malignant potentials of different types of hyperplasia. This paper classifies 4 types of hyperplasia: 1) cystic hyperplasia, which has the risk of malignant change of less than 2%; 2) adenomatous hyperplasia, which has a risk of malignant change from 12-25%; 3) atypical hyperplasia, which has a malignancy potential of 45%; and 4) carcinoma in situ, which is malignant. The following conditions are discussed as they are associated with endometrial hyperplasia and adenocarcinoma: 1) obesity; 2) anovulation; 3) late menopause; 4) Stein-Leventhal syndrome; 5) functioning ovarian tumors; and 6) diabetes history. In addition hypertension and cancers of the breast and ovary occur more often with endometrial cancer than would be expected by chance. The remainder of the paper discusses the administration of exogenous estrogens unopposed, exogenous progestins, and their concurrent use, especially in controlling menopausal symptoms. Prevention, diagnosis, and treatment of hyperplasia are discussed. In terms of prevention, a study showed that low-dose cyclical Premarin (.625 mg) resulted in an incidence of hyperplasia of 7% and with higher doses (1.25 mg) rose to 15%. The addition of d-norgestrel for 7 days to the high dose of Premarin reduced incidences to 3%, whereas estrogen plus low-dose norethindrone resulted in 0% incidence of cystic hyperplasia. It is recommended that the unopposed use of estrogens be avoided if possible, although short-term therapy up to 6 months is probably safe. Longer term therapy must have added progestogen, and endometrial sampling in the form of Vabra curettage should be performed every year in patients taking unopposed estrogens and every 3 years in patients taking combined estrogen therapy.^ieng

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.

A study of the benefits and acceptability of ambulation in spontaneous labour.

A prospective study of 300 consecutive deliveries has been made to assess the benefits and acceptability of ambulation during spontaneous labour. Ambulation during the first stage occurred in 48 patients with 55 non-ambulant patients acting as controls. No difference in the length of first or second stage, incidence of fetal distress or mode of delivery was observed. In spite of the lack of apparent advantage to the fetal condition, ambulation was acceptable to both patients and nursing staff and should not be discouraged.

Outcome of normal and dysfunctional labor in different racial groups.

Spontaneous labor in patients of different racial groups has been studied relating progress and outcome to whether labor was dysfunctional as defined by the partogram and action line. Forty-three percent of primigravidas and 17.6 to 25.8% of multigravidas passed the action line and had a lower admission cervical dilatation and a longer observed first stage than those patients whose labor progress remained to the left of the action line. White and black primigravidas whose labor progressed to the right of the action line had lower 1 and 5 minute Apgar scores and delivered heavier babies than those to the left. The cesarean section rates were 1.6% and 1.4% (left) and 7.6% and 18.2% (right) in white and black primigravidas, respectively. The cesarean section rate was significantly higher in black primigravidas irrespective of the relationship to the action line due to the high incidence of the complications of hypertension such as fetal distress and abruptio placentae in those in normal labor as well as those in dysfunctional labor due to cephalopelvic disproportion in those patients whose cervimetric progress went to the right of the action line.

Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy.

The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without progestagen. Two courses of 21 days of 5 mg norethisterone daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy. Cyclical low-dose oestrogen therapy with 7--13 days of progestagen does not seem to increase the risk of endometrial hyperplasia or carcinoma.

Relation between plasma hormone profiles, symptoms, and response to oestrogen treatment in women approaching the menopause.

Out of a consecutive series of 300 patients seen at a menopause clinic, 82 complained of symptoms generally associated with the climacteric, although they were still menstruating. Vasomotor disturbances were absent in 42 of these patients (group 1) and present in 40 (group 2). Headaches, insomnia, and dyspareunia were the most common complaints among the women with vasomotor symptoms, whereas loss of libido and depression predominated in those without. Conjugated equine oestrogens (Premarin) 1.25 mg daily given for three weeks out of four relieved nearly all symptoms in group 2, but in group 1 the response was disappointing. The mean plasma oestradiol concentration in women with vasomotor symptoms was significantly lower than that observed during days 1-10 of the menstrual cycle, but plasma testosterone values were not significantly different from those observed in younger women. Plasma follicle-stimulating hormone (FSH) and luteinising hormone (LH) concentrations were similar to those seen after the menopause. Concentrations of these hormones in the women without vasomotor symptoms were similar to those in the younger, regularly menstruating women. After six months of oestrogen treatment patients in group 2 had a 2.1-fold increase in mean plasma oestradiol concentration, and plasma FSH and LH concentrations were reduced to 39% and 66% of their pretreatment values respectively; in group 1, however, no such pronounced changes occurred. High concentrations of FSH were present in patients with oestrogen-responsive symptoms, 15 U/1 being the diagnostic cut-off point. This measurement in the presence of characteristic symptoms therefore constitutes the best method of selecting patients for oestrogen-replacement therapy.

PIP: Of 300 menopausal patients, 82 experienced climacteric symptoms, with vasomotor disturbances absent in 42 (Group 1) and present in 40(Group 2). Group 2 patients commonly complained of headaches, insomnia and dyspareunia, while Group 1 complained mostly of loss of libido and depression. Group 2 was managed rather successfully with treatment of conjugated equine estrogens (Premarin) daily for 3 weeks; Group 1 was given the same treatment but the response was disappointing. Women with vasomotor symptoms exhibited a lower, mean plasma estradiol concentration compared with that observed during days 1-10 of the menstrual cycle. Concenerations of FSH (Plasma follicle stimulating hormone) and LH (luteinizing hormone) in women with vasomotor symptoms were similar to those of younger, regularly menstruating women. Group 2 patients treated for 6 months with estrogen had a 2.1 fold increase in mean plasma estradiol concentration and 39% and 66% reduction of pretreatment plasma FSH and LH concentrations, respectively; Group 1 did not exhibit such changes. Patients with estrogen-responsive symptoms exhibited high concentrations of FSH (15 U/1 was the diagnostic cut-off point). Effective patient selection for estrogen replacement therapy can be achieved by using this measurement in the presence of characteristic symptoms.