Progestogen Phase Research Articles

Analysis of oxidative stress during the menstrual cycle

BackgroundFew data concerning the oxidative stress (OS) in plasma during the entire menstrual cycle of eumenorrheic women are available.MethodsOS was assessed in 20 healthy volunteers during the phase of the menstrual cycle by determining the plasmatic hydroperoxides levels (d-ROMs test). The assessment was performed every three days, starting from the first day (t1) up the end of the menstrual phase (t27). Concomitantly, the estrogen (E2) and progestin (P4) levels were determined at the same time intervals.ResultsFrom a base value (t1) of 284 +/− 38.0 CARR.U., which is essentially within the normal range (<300 Carratelli units or CARR.U.), the OS levels progressively increased to 378 +/− 115 CARR.U. at t15, and then slightly decreased over the subsequent time but with average values >300 CARR.U. Analysis of the E2 levels showed that the maximum OS values were noticed near the estrogen peak, while remaining above the base levels, and then decreased during the progestin phase until returning to normal at the end of the menstrual cycle.ConclusionsIt may concludes that the healthy women go into OS for 2/3 of the menstrual cycle.

Low doses of cocaine decrease, and high doses increase, anxiety-like behavior and brain progestogen levels among intact rats

There are sex and hormonal differences in response to cocaine that have been demonstrated in people and animal models. Cocaine can alter secretion of progestogens, such as progesterone (P), and its neuroactive metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP). However, little research has been done on the neuroendocrine effects in the initiation phase of cocaine use. We hypothesize that some sex/hormonal differences in initiation phase responses to cocaine may be related to formation of progestogens. To investigate the role of progestogens in sex differences in response to acute cocaine, male and female rats in the high (proestrous) or low (diestrous) progestogen phase of the estrous cycle were administered cocaine (0, 5, 10, or 20 mg/kg, IP). We examined cocaine's acute neuroendocrine effects on P and 3α,5α-THP levels, as well as its effects on acute psychomotor stimulation, anxiety, and sexual behaviors. Among rats that had P and/or 3α,5α-THP levels increased in response to cocaine, enhanced acute psychomotor stimulation was observed. Results suggest that cocaine produces U-shaped curves for progestogens, and anxiety-like behaviors. Male rats were less susceptible to these effects of cocaine than were proestrous or diestrous female rats. However, cocaine's disruption of sexual behaviors was similar among males and proestrous females. These data suggest a complex interaction between hormonal milieu and the neuroendocrine and behavioral effects of cocaine.

Single Injection Depot Progesterone Prior to Surgery and Survival in Women with Operable Breast Cancer: A Randomized Controlled Trial.

Abstract Background:The relationship between timing of surgery during menstrual cycle and survival in women with operable breast cancer (OBC) has been a subject of much debate. A meta-analysis of 37 retrospective studies revealed a modest survival benefit of 15%±8(2P=0.003) for those operated during progestogenic phase, whereas three prospective studies did not show any difference. Another meta-analysis of effect of circulating progesterone at the time of surgery showed a 53%±4(2P&amp;lt;0.001) improvement in survival when progesterone levels were high. The effect was confined to women with tumours that harboured lymph node metastasis(LN mets). We tested the effect of pharmacological induction of a progestogenic environment at the time of surgery on survival in women with OBC in a randomized controlled trial.Methods: One thousand women with OBC stratified by menopausal status and tumour size were randomly assigned to standard treatment (control) or an additional injection of depot preparation of hydroxy-progesterone(500 mg) 4-14 days prior to definitive surgery (treatment). Standard international guidelines were followed for adjuvant treatment. The primary endpoints were local, regional or distant recurrence(DFS) and secondary endpoint was death. Univariate comparison between treatment and control groups was performed using Kaplan Meier analysis and log rank test. A planned stratified analysis by lymph node status was also carried out. Cox proportional hazard model was used to assess the impact of tumour size, LN mets, menopausal status, treatment and an interaction between treatment and LN mets on DFS.Results: At median follow up of 65 months, 273 recurrences and 188 deaths have been recorded. In 982 eligible women DFS was 74% in treatment group and 70% in control group (RR=0.82, CI=0.67-1.08, P=0.195) while in women with LN mets DFS was 64.7% in treatment group and 54.6% in control group (RR=0.73,CI=0.54-0.97 p = 0.03). OAS was 81.5% in treatment arm and 80.2% in control arm (OR=0.94,CI=0.70-1.25, p=0.65) and, in women with LN mets, 76.3% in treatment arm and 69.9 % in control group (RR=0.74,CI=0.52-1.06, p=0.104). A Cox proportional hazard model for DFS revealed a significant impact of lymph node metastases (RR=2.22, CI=1.58-3.11, p=0.0005], hormone receptor positivity (RR=1.47,CI=1.15-1.87, p=0.002), and the interaction term between treatment and lymph node metastases (RR=1.15, CI=1.01-1.32, p=0.039) .Conclusions:A progestogenic milieu at the time of surgery significantly improves DFS in women with OBC and lymph node metastases. This could be a simple and inexpensive intervention for women with OBC, more so in developing world where lymph node positivity is high. A short term pre-operative intervention could be a novel window to explore impact of new drugs in a cost-effective manner. [NCT00123669]. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 72.

Colposcopically observed vascular changes in the cervix in relation to the hormonal levels and menstrual cycle.

We assessed colposcopically observed vascular changes occurring in the cervix in relation to cyclical hormonal variation in healthy women. Thirty women with regular menstrual cycles and willing to remain sexually abstinent during a menstrual cycle were enrolled. Colposcopy was performed during the peak of the estrogen and progesterone levels. The mean (+/-SD) diameter of the largest visible blood vessel differed significantly between the estrogenic phase (0.38 +/- 0.14 mm) as compared with the progestogenic phase (0.47 +/- 0.12 mm; p <.01). The blood vessels were more prominent and dense and had a well-defined outline during the progestogenic phase than the estrogenic phase; however, these differences were not statistically significant. There was borderline increase in the interleukin 8 level during the estrogenic phase. Physiological changes of increased vascularity of the cervix observed colposcopically during the progestogenic phase are normal. If such changes do not correspond to the menstrual cycle phase in women using vaginal microbicides in early-phase clinical trials, presence of inflammatory markers should be evaluated. Elevated interleukin 8 during the estrogenic phase needs further evaluation.

Adverse mood effects during postmenopausal hormone treatment in relation to personality traits

Objective When postmenopausal women are treated with sequential hormone therapy (HT), cyclical mood swings similar to symptoms seen in the premenstrual dysphoric disorder (PMDD) are described. Women with a history of premenstrual symptoms (PMS) seem to respond differently to the addition of a progestin to estrogen than women without previous PMS. This study aimed to investigate personality traits and daily mood symptoms in women with a history of PMS and women without, while treated with estrogen and sequential progestin.Methods A total of 106 women, who participated in clinical trials designed to evaluate mood and physical responses to sequential estrogen and progestin therapy, filled out the Karolinska Personality Scale (KSP) form, before entering the studies. The treatment consisted of 2 mg estradiol valerate continuously, with an addition of 10 mg medroxyprogesterone acetate (MPA) during the last 12 days of the 28-day cycle. Subjects kept daily symptom ratings using a validated symptom scale during these two treatment cycles, and these were used for the analyses. The study-groups were stratified for a history of PMS or not, appearance of progestin-induced adverse mood effects or not, and symptom cyclicity or not.Results There was a significant co-variation between the women who reported the highest negative mood scores during the addition of progestin to estrogen and a history of PMS. Women with PMS history reported different personality characteristics as having higher scores of anxiety symptoms of muscular tension, feeling more indirect aggression and lack of impulse control, and being less satisfied with their lives or childhood, compared to women without a PMS history. Women who reported the most intense negative mood symptoms during the progestin phase reported more somatic anxiety, an aim to avoid monotony, a lower satisfaction with life or childhood, and higher scores of indirect aggression and irritability.Conclusions Women with a history of PMS and women with a high anxiety-related personality might respond with adverse mood effects to a combination of estrogen and sequential progestin and therefore a thorough evaluation should be made, at the consultation for hormone therapy, of mood benefits or disadvantages before initiation of treatment and there should be a close follow-up after.

Effects of dydrogesterone and norethisterone, in combination with oestradiol, on lipoproteins and inflammatory markers in postmenopausal women

Objective The lack of cardiovascular benefit from postmenopausal hormone replacement therapy (HRT) in randomised controlled trials is not readily explained. The androgenic properties of progestogens could be crucial in understanding the results of these studies, all of which employed medroxyprogesterone. We have previously reported that medroxyprogesterone has some androgenic effects intermediate between those of the more androgenic norethisterone and the less androgenic desogestrel. To examine the androgenicity of progestogens further, we compared the effects of dydrogesterone (DGT) that is even less androgenic than desogestrel, and norethisterone (NET), on lipoproteins and inflammatory markers while maintaining the same oestrogen dose. Method In a crossover trial, 25 non-hysterectomised postmenopausal women were randomised to two preparations of HRT each for three 28-day treatment cycles. Both HRT regimens comprised oestradiol (1 mg). One also included DGT (10 mg) and the other NET (1 mg). Oestradiol was taken continuously and the progestogens sequentially. Measurements were made at baseline and on the last day of the oestradiol phase and the last day of the progestogen phase in the third treatment cycle of each regimen. Results NET was more effective than DGT in significantly reducing lipoprotein (a) ( p < 0.05). NET was, however, associated with significantly lower levels of high-density lipoprotein (HDL) cholesterol ( p = 0.001) and triglycerides ( p < 0.05). NET was less effective in opposing the oestrogen-related increase in C-reactive protein (CRP). Interleukin-6 levels did not change with either progestogen. Conclusion The effect of androgenic progestogens on cardiovascular risk factors may not be as deleterious as previously assumed, especially if the lower HDL levels result from more efficient reverse cholesterol transport. The hormone related rise in C-reactive protein , without a corresponding increase in interleukin-6, may not represent a systemic inflammatory response.

Endogenous sex hormones affect the mutagen-induced chromosome damage by altering a caffeine-sensitive checkpoint

In the present study we analysed the effect of endogenous sex hormones on the SCE frequencies induced in vitro by mitomycin C (MMC), a bifunctional alkylating agent producing high chromosome damage and mitotic arrest. The analysis has been performed on lymphocytes obtained at three different phases of menstrual cycle, from women with regular cycle and hormones dosage. At all phases we further analysed the effect of a post-treatment with caffeine, an agent that it is known to overrride the DNA damage checkpoints. After MMC, the cultures obtained at ovulation and luteal phases have SCE frequencies statistically higher than the cultures obtained at the progestogenic phase, showing increases of 15 and 25%, respectively. After caffeine, the MMC treated cultures which were set up at the progestogenic phase show a high potentiation of SCE frequencies (28%) whereas the treated cultures set up at ovulatory and luteal phases show little or no potentiation. These findings demonstrate that the endogenous hormones greatly modulate the SCE frequencies induced by the mutagen; they also indicate that hormones action competes with the caffeine effect. Caffeine acts by abrogating the mitotic arrest produced by DNA damage and induced cells with a higher chromosome damage into a premature mitosis. Our findings suggest that endogenous hormones could overcome the checkpoint controls activated in cells after mutagenic exposure. This action may be an epigenetic mechanism relevant in hormone carcinogenesis.

Endometrial safety and tolerability of triphasic sequential hormone replacement estradiol valerate/medroxyprogesterone acetate therapy regimen

Objective Two randomized comparative multicenter studies were conducted to establish the endometrial safety and tolerability of a triphasic sequential hormone replacement estradiol valerate/medroxyprogesterone acetate (E2V/MPA) therapy regimen.Methods Study 1 was a randomized, double-blind, clinical phase III study in 399 postmenopausal women, following parallel-group design with two groups. The duration of study treatment was 12 or 13 cycles of 28 days. A double-dummy technique was used to ensure blinding in the study. The investigational drugs were E2V/MPA triphasic and E2V/MPA biphasic (Diviseq® and Divina®, respectively; Orion Pharma).In study 2, a total of 341 subjects were randomly allocated by computer into two parallel groups receiving either E2V/MPA or estradiol/norethisterone acetate triphasic (E2/NETA, Trisequens?; Novo Nordisk A/S) for 12–13 cycles. The study was an open, clinical phase III trial with a randomized, parallel-group design.Endometrial biopsies combined with transvaginal ultrasound were undertaken before and at the end of treatment during the progestogen phase. Bleeding patterns and symptom control were assessed throughout both studies.Results E2V/MPA triphasic was found to have similar endometrial effects and bleeding patterns to those with E2V/MPA biphasic and E2/NETA triphasic. Climacteric symptoms were relieved as quickly and effectively as with the two comparator treatments. No adverse drug reactions specific to E2V/MPA triphasic were observed. At the end of the study, the proportions of secretory samples were 67.1% for the combined E2V/MPA triphasic groups, 65.6% for the E2V/MPA biphasic group and 71.6% for the E2/NETA triphasic group. One case of hyperplasia occurred in the E2V/MPA triphasic group. Thus the incidence of hyperplasia for the combined groups was 0.33%.Conclusions The triphasic E2V/MPA regimen was well tolerated and produced endometrial effects similar to those of the two comparators. Extending estrogen during the so-called treatment-free week with a lower dose of estradiol was effective in controlling vasomotor symptoms.

Exploration of cyclical changes in memory and mood in postmenopausal women taking sequential combined oestrogen and progestogen preparations.

To investigate the effect of progesterone on cognitive function, mood, sleep quality and libido when added to oestrogen in sequential combined hormonal replacement therapy regimens. Observational study over three hormonal replacement therapy cycles. Menopause Centre of Ospedale Maternità, Bologna, Italy. Twenty-three postmenopausal women with an average of 70 months of amenorrhoea (range 12 to 234 months) on different sequential combined hormonal replacement therapy regimen for an average of 15 months (range 3-48) months. Psychological testing for memory, mood, sleep quality and libido during the oestrogen only part of the cycle compared with the oestrogen-progestogen part of the cycle. Twenty women completed the six visits of the trial. The addition of progestogens to oestrogen appeared to benefit memory (P < 0.01) but worsened mood (P < 0.005). There was no evidence of change in other parameters such as sleep quality or libido. The addition of progestogens improved memory above what was obtained with oestrogen alone. This effect did not depend on an improvement of mood since the latter worsened during the progestogenic phase of an hormonal replacement therapy cycle. Progestogen added to oestrogen did not significantly influence sleep or libido.

Exploration of cyclical changes in memory and mood in postmenopausal women taking sequential combined oestrogen and progestogen preparations

Objective To investigate the effect of progesterone on cognitive function, mood, sleep quality and libido when added to oestrogen in sequential combined hormonal replacement therapy regimens. Design Observational study over three hormonal replacement therapy cycles. Setting Menopause Centre of Ospedale Maternità, Bologna, Italy. Population Twenty-three postmenopausal women with an average of 70 months of amenorrhoea (range 12 to 234 months) on different sequential combined hormonal replacement therapy regimen for an average of 15 months (range 3–48) months. Methods Psychological testing for memory, mood, sleep quality and libido during the oestrogen only part of the cycle compared with the oestrogen-progestogen part of the cycle. Results Twenty women completed the six visits of the trial. The addition of progestogens to oestrogen appeared to benefit memory ( P<0.01) but worsened mood ( P<0.005). There was no evidence of change in other parameters such as sleep quality or libido. Conclusion The addition of progestogens improved memory above what was obtained with oestrogen alone. This effect did not depend on an improvement of mood since the latter worsened during the progestogenic phase of an hormonal replacement therapy cycle. Progestogen added to oestrogen did not significantly influence sleep or libido.

Negative mood changes during hormone replacement therapy: A comparison between two progestogens

Objective: The aim of this study was to compare side effects of medroxyprogesterone acetate and norethindrone acetate during postmenopausal hormone replacement therapy in women with and without a history of premenstrual syndrome. Study Design: Fifty-one postmenopausal women were randomly selected in a double-blind crossover study. The women received 2 mg of estradiol continuously during five 28-day cycles and 10 mg of medroxyprogesterone or 1 mg of norethindrone sequentially for 12 days of each cycle. Daily symptom rating scales were kept. Results: The women showed cyclic changes, with negative mood and physical symptoms culminating during the late progestogen phase and positive mood during the estrogen-only phase. Symptoms declined with time but remained after 5 months. Women with a history of premenstrual syndrome responded strongly to both progestogens. Medroxyprogesterone acetate induced less negative and more positive mood symptoms than norethindrone in women with no history of premenstrual syndrome. In both groups medroxyprogesterone caused more physical symptoms than norethindrone. Conclusion: The addition of medroxyprogesterone to estrogen is preferable to norethindrone with respect to mood symptoms in women without a history of premenstrual syndrome. (Am J Obstet Gynecol 2000;183:1419-26.)

Efficacy and tolerability of fully transdermal hormone replacement in sequential or continuous therapy at two doses of progestogen in postmenopausal women

Objectives: Two randomized open-label studies were performed to evaluate fully transdermal hormone replacement therapy (HRT) with oestradiol (E 2) and norethisterone acetate (NETA) in postmenopausal women. Methods: Both hormones were delivered by transdermal matrix patches changed twice weekly. Subjects received E 2, 50 μg/day and NETA, 170 μg/day or 350 μg/day, either continuously or sequentially. A one-year study (13 cycles of 28 days), including a reference regimen of transdermal E 2 and sequential oral progestogen, was followed by a continuation study for a further year in 367 women. Results: All regimens were highly and equally effective in the prevention of hot flushes. The fully transdermal regimens were associated with beneficial changes in the lipid profile. The sequential regimens provided effective scheduling of bleeding around the end of the progestogen phase. The continuous regimens were associated with irregular bleeding, which was rarely severe, and a gradually increasing incidence of amenorrhoea. With sequential or continuous therapy, bleeding was less severe at the lower dose of progestogen than at the higher dose. No endometrial hyperplasia was detected by biopsy in any treatment group. One serous endometrial carcinoma and one endometrial adenocarcinoma were detected. An endometrial thickness >5 mm did not predict the presence of hyperplasia at biopsy. Hormone-related adverse events were typical of those expected for HRT and dermal tolerability of the patches was good. Conclusions: Fully transdermal sequential or continuous HRT is effective and well tolerated in postmenopausal women. The lower dose of NETA may be preferable, because it confers adequate endometrial protection at a lower dose of progestogen.

Progestins and menopause: epidemiological studies of risks of endometrial and breast cancer

Estrogen replacement therapy (ERT) increases a woman’s risk of developing endometrial cancer approximately 120% for each 5 years of use. ERT increases a woman’s risk of developing breast cancer approximately 10% for each 5 years of use. To reduce the greatly increased endometrial cancer risk, progestins have been added to ERT (estrogen-progestin replacement therapy; EPRT) for between 5 and 15 days (usually 7 or 10 days) per month in a sequential fashion (sequential EPRT; SEPRT) or with each dose of ERT (continuous-combined EPRT; CEPRT). We conducted two large case-control studies in postmenopausal women in Los Angeles to evaluate the effects of these changes on endometrial and breast cancer risks. As expected CEPRT was not associated with any increased risk of endometrial cancer. SEPRT with the progestin being given for 10 days per month also did not increase endometrial cancer risk. SEPRT with the progestin being given for 7 days per month did increase endometrial cancer risk with only a relatively slight reduction in risk compared to ERT effectively proportional to the reduction in the number of days of unopposed estrogen. The sharp contrast between the effects of 7 days and 10 days of progestin in SEPRT suggests that the extent of endometrial sloughing or of ‘terminal’ differentiation at the completion of the progestin phase may play a critical role in determining endometrial cancer risk. This may provide an explanation of why endometrial cancer risk increases so sharply with age in young women even in countries where obesity-associated anovulation is very uncommon; extended periods of unopposed estrogen is not an explanation but less than 10 days of an ‘adequate’ progesterone level may be. EPRT significantly increased the risk of breast cancer. EPRT was associated with an approximately 24% increase in risk for each 5 years of use; the effect was some 2 1 2 -fold greater than the effect of ERT, which we had previously predicted on theoretical grounds. This effect could also be predicted from the results on mammographic densities seen in the PEPI randomized trial of different forms of hormone replacement therapy (HRT). In the PEPI trial EPRT increased mammographic densities to a much greater extent than ERT. Progestins need to be given to protect the endometrium. They need to be delivered to the endometrium in a manner that will have the least effect on the breast. This can be carried out by using a vaginal or direct endometrial route of administration. The vaginal route will provide adequate endometrial progestin levels with low blood levels so that the effects of the progestin on the breast should be small; with the direct endometrial route the blood progestin levels are even lower, and the effects of the progestin on the breast will be effectively zero. If this is unacceptable to a woman, then giving progestins by mouth (or transdermally) for 10 days every 3 to 4 months should provide satisfactory protection of the endometrium when used with standard-dose conjugated estrogen (CE). This regimen has much less effect on the breast than monthly SEPRT or CEPRT. Two clinical trials of 10 mg per day of MPA for 14 days every 3 months and 0.625 mg/day of CE have been published. Both studies suggest that this approach may be satisfactory in that the extent of hyperplasia was minimal. More studies of this approach are urgently needed.

The effect of hormone replacement therapy on the immunoreactive concentrations in the endometrium of oestrogen and progesterone receptor, heat shock protein 27, and human beta-lactoglobulin.

We determined the expression of oestrogen receptor (ER), progesterone receptor (PR), heat shock protein 27 (HSP27) and human beta-lactoglobulin in the endometrium under hormone replacement therapy (HRT). The immunohistochemical expression during the late progestogenic phase of sequential HRT was compared semi-quantitatively and using image analysis, to the early, mid-, and late luteal phase of the physiological cycle. Under sequential HRT, smaller glands were positive for the ER but larger glands with more advanced secretory features were negative. ER expression was lower in the stroma under HRT, and the difference was statistically significant compared with the early luteal phase (P < 0.05). Expression of HSP27 under HRT was lower in the epithelium but higher in the stroma compared with the physiological luteal phase. Epithelial PR expression was lower under HRT compared with the early, but not the mid- or the late luteal phase. The number of PR-positive stromal cells under HRT was lower compared with the physiological cycle, and the difference was statistically significant in comparison with the early luteal phase (P < 0.05). The glandular area expressing human beta-lactoglobulin during the late progestogenic phase was statistically significantly higher compared with the early, but lower in comparison with the mid- or the late luteal phase (P < 0.05). The study demonstrates a sub-physiological progestogenic response superimposed on evidence of a hypo-oestrogenism, and a differential response in the epithelium and stroma.

The effect of hormone replacement therapy on the number and the proliferation index of endometrial leukocytes.

This study aimed to determine the changes in endometrial leukocyte subpopulations under sequential hormone replacement therapy (HRT) during the late progestogenic phase. The number of leukocytes was determined using immunohistochemistry utilizing monoclonal antibodies to CD45 (total leukocytes), CD56 (endometrial granulated lymphocytes), CD3 (T-cells), and CD68 (macrophages). Leukocyte proliferation was demonstrated using in-situ hybridization with a histone probe, and the proliferation index was determined using double labelling for Ki67 (Mib1). Compared to the corresponding phase of the physiological cycle, sequential HRT-treated endometrium exhibited a 95% increase in CD45(+) cells (P < 0.05), a 130% increase in CD56(+) cells (P < 0.05), and a 113% increase in CD3 cells. There was a non-statistically significant drop in the number of CD68(+) cells. The number of proliferating leukocytes increased in sequential HRT endometrium.

Progestins

The history of progesterone and hormone replacement therapy goes back to 1934 when Butenandt obtained crystalline progesterone and Kaufmann started to treat ovariectomized women with both estrogens and progesterone (Table 1). Today synthetic perorally active 19-nortestosterone and 17-α-hydroxyprogesterone derivatives are used in addition to contraception and hormone replacement therapy in a variety of gynecological disorders. In hormone replacement therapy progestin is added only to prevent development of hyperplasia of the endometrium and its consequences. However, because progestins may cause both subjective and metabolic adverse effects minimum effective antiproliferative doses are recommended. The duration of the progestin phase cannot be shortened to less than 10 days whereas the frequency of administration apparently can be reduced without increased risk of hyperplasia. Development of new modes of administration may further help in reduction of the doses.

Progestins

The history of progesterone and hormone replacement therapy goes back to 1934 when Butenandt obtained crystalline progesterone and Kaufmann started to treat ovariectomized women with both estrogens and progesterone (Table 1). Today synthetic perorally active 19-nortestosterone and 17-α-hydroxyprogesterone derivatives are used in addition to contraception and hormone replacement therapy in a variety of gynecological disorders. In hormone replacement therapy progestin is added only to prevent development of hyperplasia of the endometrium and its consequences. However, because progestins may cause both subjective and metabolic adverse effects minimum effective antiproliferative doses are recommended. The duration of the progestin phase cannot be shortened to less than 10 days whereas the frequency of administration apparently can be reduced without increased risk of hyperplasia. Development of new modes of administration may further help in reduction of the doses.

Cyclic alterations in rhesus monkey endometrium by scanning electron microscopy.

The present study was undertaken to correlate the surface topography of endometrium with altered concentrations of circulating steroids during different phases of the artificially-induced menstrual cycle. Scanning electron microscopy demonstrated that oestradiol during the oestrogenic phase induces an increase in the number of ciliated cells and the size of microvilli; by contrast, progesterone, in addition to inducing secretory activity in non-ciliated cells, had a negative effect on oestradiol-dependent morphological characteristics of ciliated cells, causing a reduction in cell number and deciliation, and inducing drooping of cilia during the progestogenic phase of the artificially-induced menstrual cycle. In addition, surface and glandular epithelial cells both actively participate in restoration of the endometrial surface during the menstrual phase, an event which parallels endometrial shedding.

Estrogen and progestin effects in human breast carcinogenesis

The influences of estrogen and progestin on human mammary neoplasia are reviewed with a view to identifying what is known about their effects. Estrogens promote growth of established cancer and pharmacological levels of progestins induce remission. In vivo, highest proliferation of histologically normal mammary epithelium occurs in the progestogenic phase of the menstrual cycle or under the progestogenic influence of oral contraceptives. Little additional hard data exist to indicate whether progestins promote or inhibit human mammary carcinogenesis. Effects on proliferation, steroid receptor content and development are discussed together with interpretation of epidemiological data on risk factors that have hormonal components. Progestins may not be the benign or beneficial agents previously supposed, and there are virtually no data to suggest that they are antiestrogenic. It is hypothesized that carcinogenesis may be accompanied by increased sensitivity to estrogen, which provides a growth advantage to the tumor by maximizing use of the low estrogen concentrations encountered in the postmenopausal state.

5 Oestrogens and atherosclerotic vascular disease—lipid factors

Cardiovascular disease remains the major cause of death for postmenopausal women in Western societies. The majority of epidemiological studies indicate that postmenopausal oestrogen replacement therapy is associated with a 50% reduction in the risk of cardiovascular disease, with much of the reduction being mediated by changes in the plasma concentration of cholesterol within high and low density lipoproteins. In addition to favourably influencing the plasma concentration of lipoproteins, oestrogens also influence the complex metabolism of lipoproteins in the arterial wall, helping to impede the formation of the atherosclerotic plaque. Whilst oestrogens alter endothelial function, vascular reactivity and fibrinolysis, these changes are also seen with reduction of LDL cholesterol and may partly reflect the altered concentration of plasma lipoproteins induced by oestrogens. Oral oestrogens have substantially greater favourable effects on LDL and HDL cholesterol than their transdermal counterparts but also result in greater hypertriglyceridaemia. Most progestogens antagonize the beneficial effects of oestrogens on lipoproteins in a dose-dependent manner; however, cyclical use of low doses of progestogens with an oral oestrogen generally retains a net beneficial effect. Lipoprotein levels fluctuate during cyclical therapy, the most adverse changes being noted at the end of the progestogen phase. Lipoprotein concentrations are constant during continuous combined regimens which have the potential for more prolonged exposure to an adverse progestational effect. Despite adverse effects on the lipoprotein profile, animal studies suggest that progestogens do not substantially reverse the beneficial effects of oestrogens on the development of atherosclerosis. Finally, oestrogen therapy may be useful in the management of postmenopausal women with hyperlipidaemia, and also in the secondary prevention of clinical sequelae in women with established atherosclerosis.