Dose dependent response of symptoms, pituitary, and bone to transdermal oestrogen in postmenopausal women.
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Administration, Cutaneous↗
Biomedical subjects
M I Whitehead
Publications and source records attributed to M I Whitehead.
Controversies concerning the safety of estrogen replacement therapy.
Unopposed estrogen replacement is known to cause endometrial carcinoma in a small percentage of postmenopausal women, but the effects on ovarian and breast tissue remain uncertain. The increased risk of endometrial carcinoma seems to be related to both the dosage and duration of unopposed estrogen treatment. Until very recently, the morbidity and costs that result from the need for endometrial biopsy because of abnormal bleeding and from the need for hysterectomy due to hyperplasia have been ignored, but recent data suggest that they are likely to be considerable. Progestogens are known to protect against endometrial hyperstimulation, but the optimal duration of therapy each month and the maximally protective agent and dose remain to be determined. Estrogen replacement therapy may reduce the risk of arterial disease; however, the comparative effects of the various preparations, as well as their respective mechanisms of action, must be subjected to further study.
Breast Neoplasms↗
Regional and total skeletal measurements in the early postmenopause.
In a cross-sectional study of 70 early postmenopausal women, regional bone measurements were compared with total body calcium (TBCa). Spinal and forearm trabecular bone were mainly related to age and time since menopause. In contrast, TBCa and forearm integral (cortical and trabecular) and cortical bone were unrelated to age, although the time since menopause also had some influence. Forearm integral and cortical bone measurements were quite well correlated with TBCa (r = 0.84 and 0.73, respectively, P less than 0.001). The correlation between spinal bone measurements and any of the forearm measurements, even purely trabecular bone, was weak (r less than 0.52, P less than 0.001). Our results show quite clearly that forearm bone measurements cannot be used to predict bone density in the vertebrae. Loss of ovarian function affects bone in general, and trabecular bone in particular. Bone measurements at specific anatomical sites are clearly necessary for studies of metabolic bone diseases and their response to treatment.
Adult↗
Single serum progesterone measurement in the mid-luteal phase as an index of ovulation.
Plasma progesterone levels were measured in three groups of cycles during which ultrasonic monitoring of follicular growth was performed to determine the day of follicular rupture and, thus, the mid-luteal phase when sample timing was optimal. This was in an attempt to fix accurately the lower limit of plasma progesterone in the mid-luteal phase that is associated with ovulation. Plasma progesterone levels were determined in fifteen normal cycles (group I), seventeen Clomid-treated cycles (group II) and seven conceptional cycles (group III), during which ultrasonic monitoring of follicular growth was performed. The day of sampling was also compared with the peak values of pregnanediol-3 alpha-glucuronide relative to the day of follicular rupture in corresponding cycles. This was to ascertain if sample timing was optimal. Progesterone levels in the treated cycles were generally higher than in spontaneous cycles. Results show that the mean value is statistically lower in groups I and II (t = -2.65 with 30 degrees of freedom), whereas there is no statistical difference between groups II and III or I and III. A level of 29.0 nmol/l (the lower value within 95% confidence interval in the conceptional group) is an appropriate lower index of ovulation.
Adult↗
The effects of estrogens and progestogens on the endometrium. Modern approach to treatment.
The major hazard of postmenopausal cyclic estrogen therapy is endometrial hyperstimulation. The incidence of hyperplasia is dose dependent; the incidence of carcinoma is both dose and duration dependent. The risk of carcinoma is small. Invasive procedures such as endometrial biopsy to detect those patients with hyperplasia and carcinoma are unlikely to be cost-effective and have other disadvantages. With cyclic estrogens, biopsies should be performed at regular intervals irrespective of the bleeding pattern. The possible alterations to cyclic treatments to reduce the risk of endometrial hyperstimulation have been reviewed; only progestogen addition has been shown to be effective. Maximal effects are obtained when progestogens are added for 12 to 13 days each calendar month. To reduce the risk of side effects, the minimum dose of progestogen should be prescribed, and with the nor-testosterone derivatives, a small dose of norethindrone, approximately 1 mg daily, is as effective as 5 mg daily. The smaller doses cause minimal lipid changes. Interpatient variation in response to the 17-hydroxyprogesterone derivatives can occur, and at high doses, adverse lipid effects have been reported. With sequential estrogen/progestogen therapies, the endometrial histology appears to correlate with the bleeding pattern, thereby, perhaps, obviating the need for biopsy. The development of regimens to induce endometrial atrophy and amenorrhea is suboptimal, and further research is required.
Drug Administration Schedule↗
Increased concentration of circulating calcitonin gene related peptide during normal human pregnancy.
Calcitonin gene related peptide is an extremely potent vasoactive peptide that causes profound vasodilatation in man. Its distribution in perivascular nerves suggests that one of its functions may be the regulation of peripheral vascular tone. Pregnancy is a physiological condition in which there are major haemodynamic changes. An increase in plasma volume of about 40% necessitates changes in peripheral vascular tone. In a cross sectional study plasma concentrations of immunoreactive calcitonin gene related peptide were measured throughout normal pregnancy and at five to seven days post partum. Calcitonin gene related peptide concentrations were significantly increased throughout pregnancy but fell after delivery. Calcitonin gene related peptide may participate in the physiological regulation of vasomotor tone in man.
Adolescent↗
A simple method for determining the optimal dosage of progestin in postmenopausal women receiving estrogens.
Progestin is often added to regimens of estrogen therapy in postmenopausal women to reduce the risk of endometrial hyperstimulation, but it may cause undesirable metabolic effects. Therefore, a low dosage is recommended. At present, the only way to determine whether the dosage of progestin is causing the desired secretory transformation of the endometrium is by endometrial sampling, which is invasive. We studied 102 postmenopausal women undergoing estrogen therapy who also took a progestin for 12 days each month, and we correlated the day of onset of bleeding with the endometrial histology over a three-month period. A bleeding pattern suitable for interpretation was observed in 96 women. Regardless of the preparation and dosage of the estrogen and progestin used, wholly or predominantly proliferative endometrium was always associated with bleeding on or before day 10 after the addition of progestin; wholly or predominantly secretory endometrium, or a lack of endometrial tissue, was associated with bleeding on day 11 or later. We conclude that the bleeding pattern reflected the histologic condition of the endometrium and that adjustment of the dosage of progestin so that regular bleeding is induced on or after day 11 may obviate the need for endometrial biopsy.
Adult↗
Hormone excretion during early pregnancy following spontaneous and clomiphene citrate-induced ovulation.
Endocrine changes during early pregnancy have been studied in 12 patients between days 35 and 91 from the last menstrual period. Ovulation had occurred spontaneously in five patients and was induced with clomiphene citrate (CC) in the remaining seven women. All the patients collected daily samples of early morning urine throughout the period of study; on each sample, human chorionic gonadotropin (hCG), pregnanediol-3-alpha-glucuronide (PGDG) and estrone-3-glucuronide (E1G) were measured by chemiluminescence immunoassay. No significant difference was observed between the two groups of patients with respect to the concentrations of hCG and PGDG. The excretion of E1G, however, was significantly higher in patients treated with CC. These data suggest that the induction of ovulation with CC may affect estrogen production in early pregnancy.
Adult↗
Assessment of the potency of orally administered progestins in women.
The effects of at least three doses of each of five orally administered progestins on estrogen-primed, postmenopausal endometrial biochemistry and morphologic features were analyzed. The progestins tested were norethindrone, medroxyprogesterone acetate (MPA), norgestrel, dydrogesterone, and progesterone. The dose required to elicit responses similar to those seen in premenopausal, secretory endometria was assessed for each of the parameters measured, and the relative potencies were calculated. Potencies, relative to a value of 1 for norethindrone, are L norgestrel 8 (D/L norgestrel 4), MPA 0.1, dydrogesterone 0.02, and progesterone 0.002. The dose of norethindrone required to elicit secretory phase activity was about 0.35 mg/day. These values agree with published data obtained with the use of different methods (delay of menstruation in premenopausal women, endometrial histologic features of estrogen-primed, ovariectomized women).
Administration, Oral↗
Effects of dydrogesterone on the oestrogenized postmenopausal endometrium.
Postmenopausal women receiving conjugated oestrogens 1.25 mg daily continuously were also given dydrogesterone either 5, 10 or 20 mg daily for the first 12 days of each calendar month. Endometrial tissue obtained on the sixth day of combined therapy in the third or subsequent treatment cycle was subjected to histological, ultrastructural and biochemical assessments. Dydrogesterone provoked secretory histological and ultrastructural changes within the endometrium in a dose-dependent manner. A daily dose of 5 mg produced sub-optimal responses but 10 and 20 mg daily produced effects similar to those observed in the secretory phase of the ovulatory cycle. Dydrogesterone 10 mg and 20 mg daily reduced epithelial DNA synthesis and nuclear oestradiol receptor levels to values within the secretory phase range. A dose-response relation was seen in the induction of oestradiol-17 beta and isocitrate dehydrogenase activities; hyperphysiological values were observed with 20 mg of dydrogesterone daily. This study has demonstrated that dydrogesterone exerts potent anti-oestrogenic and progestational effects on the human endometrium which are dose-related. The 10 and 20 mg doses induced responses equal to or greater than those observed in the secretory phase of the ovulatory cycle and both dosages can be recommended for use in combination with exogenous oestrogens in postmenopausal women: and they may also have a role in the management of anovulatory dysfunctional uterine bleeding.
Cell Nucleus↗
Oestriol with oestradiol verses oestradiol alone: a comparison of endometrial, symptomatic and psychological effects.
In a prospective, double-blind, randomized, cross-over trial, the effects of oral oestradiol, 2 mg daily, on the endometrial histology, frequency and severity of vaginal bleeding, and the symptomatic and psychological status of postmenopausal women were compared with those of oral oestradiol, 2 mg daily, plus oestriol, 1 mg daily. Both therapies were prescribed for 3 months on a cyclical basis. The addition of oestriol to oestradiol did not modify the endometrial response. The prevalence of proliferative/hyperplastic endometrium (64%: 9 of 14 biopsies) was similar after both treatments and there were no significant differences in either the frequency or heaviness of vaginal bleeding. Both therapies significantly reduced hot flushes, night sweats and vaginal dryness: no significant differences in effect on the symptomatic and psychological status were recorded. The addition of 1 mg of oestriol to 2 mg of oestradiol did not confer any benefit and the value of such an addition is challenged.
Adult↗
Prevention of endometrial abnormalities.
Exogenous oestrogens are highly effective in relieving not only the acute symptoms of ovarian failure, such as vasomotor instability and vaginal dryness, but also in conserving postmenopausal bone mass. However, the oestrogen doses needed to achieve these benefits also induce endometrial proliferation. The risk of endometrial hyperplasia and carcinoma are thereby increased and unopposed oestrogen therapy is associated with a high incidence of abnormal vaginal bleeding requiring appropriate, invasive investigations. The cost-effectiveness of therapy and patient compliance are likely to be correspondingly reduced. Various strategies have been proposed to try to overcome the risk of endometrial hyperstimulation and these strategies have been reviewed. Based upon the available evidence, progestogen addition appears the most sensible and has been shown to be effective. It is now clear that progestogens should, in sequential therapies, be administered for 12 days each cycle for maximum protection. Concern has been expressed that the regular withdrawal bleed induced by sequential treatment will reduce patient compliance. Progestogens have, therefore, been added in a continuous fashion to try to prevent endometrial proliferation and thereby induce amenorrhoea. The ideal continuous, oestrogen/progestogen regimen has not yet been developed: all those evaluated to date are associated with a high incidence of breakthrough bleeding which is likely to restrict their use. Progestogens can cause undesirable physical, psychological and metabolic effects. The incidence and severity of side-effects will depend upon the type of progestogen prescribed, the route of administration, and the dose. Minimum effective daily doses of certain types of progestogens have now been established in terms of endometrial protection. Regrettably, few data are available on the physical and psychological effects of these progestogen doses: more information is available on lipid and lipoprotein effects but the data are confused and, at times, contradictory. More research is urgently needed to determine which of these progestogens is most suitable for addition to postmenopausal oestrogen therapy.
Endometrial Hyperplasia↗
Absorption and metabolism of oral progesterone when administered twice daily.
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Biology↗
Is Provera the ideal progestogen for addition to postmenopausal estrogen therapy?
In a dose-ranging study, medroxyprogesterone acetate, 2.5, 5, or 10 mg daily, was given for 12 days of each calendar month to postmenopausal women also receiving conjugated estrogens, 0.625 mg daily, continuously. Endometrial biopsy specimens were taken on the sixth day of combined therapy for histologic, ultrastructural and biochemical evaluation. Medroxyprogesterone acetate induced secretory and ultrastructural changes within the endometrium, but the responses were variable and inconsistent. Suppression of epithelial deoxyribonucleic acid synthesis appeared dose-dependent. The levels of nuclear estradiol receptor, although reduced to within the secretory phase range, were not significantly lower than the values observed during the estrogen-only phase of treatment. Induction of both estradiol and isocitrate dehydrogenase activities was to within the secretory phase ranges, but the magnitude of these responses appeared less than those observed previously with other progestogens. Both morphologically and biochemically, medroxyprogesterone acetate, even at high dosage, produced suboptimal responses. Further studies are required to establish whether this is a dose-related effect.
Biopsy↗
Absorption and metabolism of oral progesterone when administered twice daily.
The absorption, metabolism, and clearance of progesterone (P) from the peripheral circulation were investigated in five postmenopausal women after oral administration of 100 mg at 9:00 A.M. and 200 mg at 9:00 P.M. for 5 consecutive days. Mean peak plasma concentrations of P were observed 2 hours after ingestion of both the 100 and 200 mg doses and were 22.7 and 47.7 nmol/l, respectively. Of the three metabolites studied, the plasma concentrations of pregnanediol-3 alpha-glucuronide were most raised by treatment; those of 17-hydroxyprogesterone were least raised. Increases in the plasma levels of 20 alpha-dihydroprogesterone were more sustained than those of P, and the plasma concentrations remained elevated at approximately 20 nmol/l for at least 12 hours after P administration. We conclude that administration of oral P 100 mg in the morning and 200 mg at night increases the circulating concentrations of P and the biologically active metabolite 20 alpha-dihydroprogesterone, and that the duration of these increases is sufficient to evoke progestational responses in responsive end-organs.
17-alpha-Hydroxyprogesterone↗
Endometrial responses to transdermal estradiol in postmenopausal women.
In prospective studies, we have determined the endometrial histologic characteristics and patterns of vaginal bleeding in 12 perimenopausal or postmenopausal women during administration of transdermal estradiol, 0.05 mg daily, given either alone or in combination with a progestogen. In the first study, we administered transdermal estradiol in cyclical fashion for 3 months. Outpatient curettage at pretreatment produced no endometrial sample or tissue too scant for assessment from 10 of the 12 patients (83%). At the end of therapy, proliferative or nonsecretory endometrium was diagnosed in nine patients (75%). Eight patients experienced treatment-related vaginal bleeding but no regular pattern, and seven patients reported breakthrough bleeding. Eight patients participated in the second study in which transdermal estradiol was administered continuously and norethindrone, 0.35 mg, was added for 12 days of each calendar month. A further curettage was performed at the end of treatment, and proliferative endometrium was the most common finding. No endometrial hyperplasia was observed. Only one patient experienced breakthrough bleeding. There were no consistent changes with time in the number of patients bleeding each month or in the duration or heaviness of the bleeding.
Administration, Topical↗
Efficacy, acceptability, and metabolic effects of transdermal estradiol in the management of postmenopausal women.
Systemic side effects that result from oral administration of estrogens to postmenopausal women may be minimized by use of the transdermal route. We administered transdermal estradiol, 0.05 mg/day, cyclically for 3 months to 12 postmenopausal and perimenopausal women to study the efficacy, acceptability, and metabolic effects of this dosage form. The results showed that transdermal estradiol significantly increased plasma levels of estradiol and estrone and urinary concentrations of estradiol conjugates, and produced significant improvement in menopausal symptoms and vaginal cytologic findings. The patches were well tolerated and no systemic side effects were reported. No clinically significant adverse biochemical changes were observed. Plasma renin substrate and renin activity were unchanged during therapy.
Administration, Topical↗