Progesterone and the premenstrual syndrome: a double blind crossover trial.

A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Moos''s menstrual distress questionnaire, Beck et al''s depression inventory, Spielberger et al''s state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.     

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.     

Efficacy of progesterone and progestogens in management of premenstrual syndrome: systematic review

ObjectiveTo evaluate the efficacy of progesterone and progestogens in the management of premenstrual syndrome.DesignSystematic review of published randomised, placebo controlled trials.ResultsOverall standardised mean difference for all trials that assessed efficacy of progesterone (by both routes of administration) was −0.028 (95% confidence interval −0.017 to −0.040). The odds ratio was 1.05 (1.03 to 1.08) in favour of progesterone, indicating no clinically important difference between progesterone and placebo. For progestogens the overall standardised mean was −0.036 (−0.014 to −0.060), which corresponds to an odds ratio of 1.07 (1.03 to 1.11) showing a statistically, but not clinically, significant improvement for women taking progestogens.ConclusionThe evidence from these meta-analyses does not support the use of progesterone or progestogens in the management of premenstrual syndrome.

What is already known on this topic

The premenstrual syndrome affects about 1.5 million women in the United KingdomThere are numerous treatment options, progesterone being one of the most strongly advocatedProgesterone and progestogens are among the most widely prescribed treatments for premenstrual syndrome in the United Kingdom and the United States

What this study adds

There is no evidence to support the claimed efficacy of progesterone in the management of premenstrual syndromeThere is insufficient evidence to make a definitive statement about progestogens, but current evidence suggests that they are not likely to be effective     

Reproductive depression

Reproductive depression is the depression in women that is related to the hormonal changes of the menstrual cycle, pregnancy and the menopause and is manifested clinically as premenstrual depression, postnatal depression and climacteric depression. These three components occur in the same vulnerable women in that a woman with depression in the menopausal transition will usually have a history of premenstrual syndrome (PMS; premenstrual dysphoric disorder [PMDD]), would have been in a good mood during pregnancy and then develop postnatal depression. When the periods return the depression becomes cyclical as PMS. These three conditions are effectively treated with transdermal estrogens which should be the first-choice therapy rather than antidepressants. Estrogens can be used together with antidepressants. The critical time to prevent long-term mood problems is the correct treatment of postnatal depression. In women with low energy and libido, often a side effect of antidepressants, the addition of transdermal testosterone is useful. These women with reproductive depression are often progesterone/progestogen intolerant and a smaller dose or duration of progestogen is a necessary compromise. Alternatively a Mirena IUS or rarely a hysterectomy is required.     

Intravenous tyramine response in migraine before and during treatment with indoramin.

We studied the response of 31 migraine sufferers (20 women, 11 men) to intravenous tyramine (the tyraminedose)pressor response test). Patients were treated either with pacebo tablets or indoramin, and alpha-adrenergic blocking agent, in a double-blind crrossover trial. We found that patients with migraine required significantly less tyramine to increase their cystolic blod pressure by 30 mm Hg when compared with matched controls. Indoramin significantly increased the amount of tyramine needed to raise the systolic blood pressure among migraine suffers and reduced the incidence of posttyramine migraine for m 46% while patients were on placebo tablets to 8% when they were receiveing indoramin. There was no association between tyramine sensitivity and a history of premenstrual or dietary migraine, nor was there a significant difference in the indierenence in the incidence of post-tyramine migrain between men women. We conclude that the intravenous tyramine test may be valuable in assessing migraine suffers who will respond to an alpha-advenergic blocking agent such as indoramin.     

Effect of the introduction of rams during the anoestrous season on the pulsatile secretion of LH in ovariectomized ewes

Introduction of rams to ovariectomized ewes treated with oestradiol implants (N = 10) increased the frequency of LH pulses from 4 X 8 to 10 X 6 pulses per 12 h. This effect was reflected by increases in mean levels of LH and the basal levels upon which the pulses were superimposed. In ewes that had not been treated with oestradiol (N = 5), there was no significant increase in pulse frequency but mean and basal levels of LH increased slightly after the introduction of rams. In a second experiment, similar effects of the introduction of rams were seen in ovariectomized ewes treated with oestradiol or oestradiol + androstenedione (N = 16), but no significant effects of the rams were observed in untreated ewes (N = 8) or ewes treated only with androstenedione (N = 7). No preovulatory surges of LH were observed in the 30-h period after the introduction of rams. It was concluded that the ram stimulus probably evokes the increase in pulse frequency by inhibiting the negative feedback action of oestradiol, and that the surge normally observed in entire ewes is dependent on the ovarian response to these pulses. However, the observation of responses in some ewes not treated with oestradiol also raises the possibility that the ram stimulus can act directly on the hypothalamic neurones that control the secretion of LH, and that this effect is enhanced in the presence of oestrogen.     

Effects of progesterone on the responses of Merino ewes to the introduction of rams during anoestrus

The effects of progesterone on the responses of Merino ewes to the introduction of rams during anoestrus were investigated in two experiments. In the first experiment, the introduction of rams induced an increase in the levels of LH in entire ewes. The mean levels increased from 0.68 +/- 0.04 ng/ml (mean +/- s.e.m.) to 4.49 +/- 1.32 ng/ml within 20 min in ewes not treated with progesterone (n = 10). In ewes bearing progesterone implants that provided a peripheral concentration of about 1.5 ng progesterone per millilitre plasma, the LH response to the introduction of rams was not prevented, but was reduced in size so that the concentration was 1.38 +/- 0.15 ng/ml after 20 min (n = 5). Progesterone treatment begun either 2 days before or 6 h after the introduction of rams and maintained for 4 days prevented ovulation. In the second experiment ovariectomized ewes were used to investigate further the mechanism by which the ram evoked increases in tonic LH secretion. In ovariectomized ewes treated with oestradiol implants, the introduction of rams increased the frequency of the LH pulses and the basal level of LH. In the absence of oestradiol there was no significant change in pulse frequency but a small increase in basal levels. Progesterone again did not prevent but reduced the responses in ewes treated with oestradiol. It is suggested that following the withdrawal of progesterone treatment, the secretion of LH pulses in response to the ram effect would be dampened. This effect could be a component of the reported long delay between the introduction of rams and the preovulatory surge of LH in ewes treated with progesterone. Continued progesterone treatment prevented ovulation, probably by blocking positive feedback by oestradiol.     

Effect of oral contraceptives and some psychological factors on the menstrual experience

This study attempts to clarify the etiology of menstrual distress by using objective measures of menstration, enlightened statistical treatment and standardized measures of psychological factors. In addition to observing the traditionally associated psychological factors, measures of health locus of control, preventive health behavior and menstrual socialization (e,g., age at menarche) are included in order to assess the relevance of attitudes towards health. 57 women (mean age=23.5 years), 1/2 of whom (29) used an oral contraceptive, completed Moos' menstrual distress questionnaire at each of the 3 menstrual phases. In addition they kept menstrual diary cards for 50 days, recording days on which menstrual blood loss occurred. During an intermenstrual phase, they completed a general information questionnaire with questions on menstrual socialization and demographic variables; Eysenck's personality inventory; the multidimensional health locus of control scale; the Bem sex role inventory; and a measure of preventive health behavior. Analyses investigating the effects of pill use and psychological factors on the incidence and intensity of menstrual distress found few significant associations between these measures, especially when symptom changes over the menstrual cycle were the dependent variables. The results generally support the notion that menstruation is a negative event for most women (2/3 of the sample). Neuroticism was found to correlate with all the premenstrual MDQ scores except the positive aspect of increased arousal, with negative affect at both menstrual and intermenstrual phases, with menstrual pain and with intermenstrual concentration. The regression analyses indicate that changes in symptoms of menstrual distress over the menstrual cycle are not well predicted by the measures investigated in this study. Of the few significant associations noted, most are explicable in common sense terms. The more objective approach adopted in this study gives little support for a psychological etiology of distres. However, it also queries the appropriateness of a physiological explanation because of the limited differences found between pill users and nonusers. The inability of locus of control scores, menstrual socialization measures and a preventive health behavior measure to contribute to the definition of a woman at risk, suggests that distress is not related to an individual's general health concepts nor perceived control. 1 aspect not investigated in this study and a topic for future research is the role of a woman's expectations on her experience.     

Flavonoid supplement improves leg health and reduces fluid retention in pre-menopausal women in a double-blind, placebo-controlled study.

Flavonoid extracts derived from plant foods have been shown to benefit certain types of fluid retention. However, no studies have investigated these compounds for use in premenstrual fluid retention, a complaint common among women with otherwise normal menstrual cycles. Therefore, we conducted a double-blind, placebo-controlled, pilot study into the effect of a daily flavonoid extract (Colladeen, 320 mg oligomeric procyanidins) on premenstrual fluid retention. Fluid retention was assessed at baseline and throughout 4 menstrual cycles of the intervention using validated questionnaires. Leg girth was also measured at baseline and at the end of the study. Thirty subjects completed the study (n = 18 active treatment; n = 12 placebo). Although no significant changes in leg girth measurements were noted, there was a significant improvement in subjective "leg health" scores after flavonoid treatment compared to placebo (p = 0.013). Furthermore, this was accompanied by an improvement in reported premenstrual fluid retention nearing significance (p = 0.066). We conclude that flavonoids supplements may provide a new therapeutic direction to counter premenstrual fluid retention and improve leg health. A larger study is now warranted.     

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.     

Intermittent compression units for severe post-phlebitic syndrome: a randomized crossover study

BACKGROUND: Although uncommon, severe post-phlebitic syndrome may be associated with persistent, intractable pain and swelling that interfere with work and leisure activities. This study was performed to determine whether intermittent compression therapy with an extremity pump benefits patients with this condition and, if so, whether the benefit is sustained. METHODS: The study was a randomized crossover trial. Over the period 1990 to 1996, all patients in the clinical thromboembolism program of an Ontario teaching hospital who had a history of deep vein thrombosis and intractable symptoms of post-phlebitic syndrome were recruited into the study. The study involved using an extremity pump twice daily for a total of 2 months (20 minutes per session). The patients were randomly assigned to use either a therapeutic pressure (50 mm Hg) or a placebo pressure (15 mm Hg) for the first month. For the second month, the patients used the other pressure. A questionnaire assessing symptoms and functional status served as the primary outcome measure and was administered at the end of each 1-month period. A symptom score was derived by summing the scores for individual questions. At the end of the 2-month study, patients were asked to indicate their treatment preference and to rate the importance of the difference between the 12 pressures. Treatment was considered successful if the patient preferred the therapeutic pressure and stated that he or she would continue using the extremity pump and that the difference between the therapeutic and placebo pressures was of at least slight importance. All other combinations of responses were considered to represent treatment failure. Patients whose treatment was classified as successful were offered the opportunity to keep the pump and to alter pressure, frequency and duration of pump use to optimize symptom management. In July 1996 the authors contacted all study participants whose treatment had been classified as successful to determine whether they were still using the pump and, if so, whether they were still deriving benefit. RESULTS: In total 15 consecutive patients (12 women and 3 men) were enrolled in the study. The symptom scores were significantly better with the therapeutic pressure (mean 16.5) than with the placebo pressure (mean 14.4) (paired t-test, p = 0.007). The treatment for 12 of the patients (80%, 95% confidence interval 52% to 96%) was considered successful. Of these, 9 patients continued to use the pump beyond the crossover study and to derive benefit. INTERPRETATION: The authors conclude that a trial of pump therapy is worthwhile for patients with severe post-phlebitic syndrome and that a sustained beneficial response can be expected in most such patients.     

Progesterone,fluid, and electrolytes in premenstrual syndrome.

Changes in mood, plasma progesterone concentration, urinary volume, sodium excretion, sodium:potassium ratio, and body weight during the menstrual cycle were determined in 18 women with premenstrual syndrome and 10 symptomless (control group) women. Plasma progesterone concentration was higher in the women with symptoms during the postovulatory phase of the cycle, and the peak progesterone concentration appeared earlier. The changes in progesterone concentration were accompanied by a natriuresis and diuresis that fell towards preovulatory values in the premenstrual phase. Sodium retention was not confined to any definite period. Mood symptoms occurred after the changes in progesterone and electrolyte concentrations. Progesterone deficiency is probably not the cause of premenstrual syndrome. Thus treatment with progesterone is probably illogical unless a deficiency is detected. Treatment should be aimed at preventing the natriuretic effect of progesterone in the postovulatory phase and the sodium-retaining and water-retaining effects of aldosterone in the premenstrual phase.     

First Non-Contingent Respiratory Biofeedback Placebo versus Contingent Biofeedback in Patients with Chronic Low Back Pain: A Randomized,Controlled, Double-Blind Trial

Previous studies reported that respiratory feedback (RFB) aids in alleviating chronic pain. However, to date, this adjunct treatment has not been rigorously tested against non-contingent (placebo) feedback. Forty-two patients with chronic low back pain were randomized to either RFB or non-contingent RFB. Both groups performed a daily 30-min home training for 15 consecutive days. A respiratory associated relaxation index (RI) was measured. Pain levels and a somatosensory profile were assessed before and after intervention. Additionally, pain levels were assessed 3 months after the end of intervention. Secondary outcome parameters included daily functioning, psychopathology, and suggestibility. T-tests showed higher and significant pain reductions for RFB, compared to non-contingent RFB. Between-group comparisons reached no significance. However, changes were more pronounced in the RFB condition, which was also true for the course of the RI and the psychopathological scores. This is the first study using a non-contingent respiratory placebo feedback in a randomized, controlled design. Within this design previous positive findings of symptom reductions in patients treated with RFB could partially replicated. Nonetheless, tendencies suggest that contingent feedback patients compared to placebo patients profit more from RFB in the long run regarding reduction of chronic pain and psychological distress.     

Quantitative analysis of oestrogen induced morphological changes in the rabbit corpus luteum

Although oestradiol is luteotropic in the rabbit, the mechanism through which oestradiol maintains the corpus luteum is unknown. To determine if ultrastructural changes in the rabbit corpus luteum accompany oestradiol treatment, corpora lutea were removed on day 10 of pseudopregnancy from hysterectomized rabbits treated with oestradiol implants and prepared for electron microscopy. Morphometric analysis was performed on luteal cells in each group (seven animals/group, four micrographs/animal) and organelle profile volumes, estimated by point-counting techniques, were expressed as a percentage of the cell volume. Morphometric analysis revealed no significant differences in nuclear, mitochondrial, lysosomal, Golgi or endoplasmic reticular volumes between control and oestradiol-treated animals. In contrast, lipid droplet volume was significantly elevated (p less than 0.001) in oestradiol-treated animals. This data suggests that an important function of oestradiol in the rabbit corpus luteum is to regulate the uptake and storage of cholesterol presumably for progesterone production.     

Self-reported symptoms among women after cosmetic breast implant and breast reduction surgery

A retrospective cohort study was performed in Sweden to evaluate the possibility that an individual symptom or constellation of illness symptoms related to silicone occurs in women after breast implant surgery. A random sample (n = 2500) of all women in the Swedish national implant registry who underwent breast augmentation surgery with alloplastic breast implants during the years 1965 through 1993 was compared with a sample (n = 3500) of women who underwent breast reduction surgery during the same period, frequency matched to the implant patients for age and calendar year at the time of surgery. In total, 65 percent of the breast implant patients (n = 1546) and 72 percent of the breast reduction patients (n = 2496) completed a self-administered questionnaire covering 28 rheumatologic and other symptoms and lifestyle and demographic factors. Practically all of the 28 symptoms inquired about were reported more often by women in the breast implant cohort, with 16 (57 percent) significantly more common in breast implant recipients. In contrast, few significant differences or consistent patterns were observed in the length of time since the implant and in the type (silicone or saline) or volume of the implant. Although women with breast implants report a multitude of symptoms more often than women who have breast reduction surgery, the lack of specificity and absence of dose-response relationships suggest that the excess of reported symptoms is not causally related to cosmetic implants.     

Population based study of fatigue and psychological distress.

OBJECTIVES--To determine the prevalence of fatigue in the general population and the factors associated with fatigue. DESIGN--Postal survey. SETTING--Six general practices in southern England. SUBJECTS--31,651 men and women aged 18-45 years registered with the practices. MAIN OUTCOME MEASURES--Responses to the 12 item general health questionnaire and a fatigue questionnaire which included self reported measures of duration, severity, and causes of fatigue. RESULTS--15,283 valid questionnaires were returned, giving a response rate of 48.3%, (64% after adjustment for inaccuracies in the practice registers). 2798 (18.3%) of respondents reported substantial fatigue lasting six months or longer. Fatigue and psychological morbidity were moderately correlated (r = 0.62). Women were more likely to complain of fatigue than men, even after adjustment for psychological distress. The commonest cited reasons for fatigue were psychosocial (40% of patients). Of 2798 patients with excessive tiredness, only 38 (1.4%) attributed this to the chronic fatigue syndrome. CONCLUSION--Fatigue is distributed as a continuous variable in the community and is closely associated with psychological morbidity.     

Nexplanon: the new implant for long-term contraception. A comprehensive descriptive review

Nexplanon(?) is a new long-term reversible contraception method. The current review is aimed to analyze the published data concerning the contraceptive effectiveness of Nexplanon(?) and its effects on reproductive function. Pharmacological properties and technical procedures of insertion and removal, as well as the efficacy and safety data available, were discussed. Possible strategies for treating Nexplanon(?)-related bleeding were also described. With regard to the future research and the future scientific developments of contraceptive implants, the possible use of Nexplanon(?) wide-ranging for the symptomatic treatment of endometriosis and premenstrual syndrome (PMS) were considered. Finally, it was defined in which women the use of Nexplanon(?) is indicated and in which it is contra-indicated.     

The effect of progesterone administration on sex hormone binding globulin binding capacity in women with severe premenstrual syndrome

Thirty-one women with severe premenstrual syndrome had low sex hormone binding globulin (SHBG) binding capacities 30.2 +/- 9.4 nmol DHT bound/l. The SHBG binding capacities rose when they were treated with three different doses of progesterone. On 400 mg (17 women) SHBG level was 45.11 +/- 11.80. On 800 mg (8 women) SHBG binding capacity rose to 64.75 +/- 14.30 and on the six women who took 1200 mg progesterone daily SHBG binding capacity was 78.5 +/- 23.10. These results are discussed.     

Skeletal effects of oral oestrogen compared with subcutaneous oestrogen and testosterone in postmenopausal women.

STUDY OBJECTIVE--To compare oral and implanted oestrogens for their effects in preventing postmenopausal osteoporosis. DESIGN--Non-randomised cohort study of postmenopausal women treated with oral or depot oestrogens and postmenopausal controls. SETTING--Gynaecological endocrine clinic in tertiary referral centre. PATIENTS--Oral treatment group of 37 postmenopausal women (mean age 57.5 years, median 8.75 years from last menstrual period), compared with 41 women given oestrogen implants (mean age 56.2 years, median 9.5 years from last menstrual period) and 36 controls (mean age 51.8 years, median 2.0 years from last menstrual period). Weight was not significantly different among the groups. INTERVENTIONS--Oral treatment group was given continuous treatment with cyclic oestrogen and progesterone preparations (Prempak C or Cycloprogynova) for a median of 8.0 years. Implant group was given subcutaneous implants of oestradiol 50 mg combined with testosterone 100 mg, on average six monthly for a median of 8.5 years. Controls were not treated. END POINT--Significant increase in bone density. MEASUREMENTS AND MAIN RESULTS--Bone density measured by dual beam photon absorptiometry was 1.02 (SD 0.13) g hydroxyapatite/cm2 in implant group versus 0.89 (0.11) in oral group (p less than 0.01) and 0.87 (0.14) in controls (p less than 0.01). Serum oestradiol concentration in implant group was (median) 725 pmol/l versus 170 pmol/l in oral group (p less than 0.01) and 99 pmol/l in controls (p less than 0.01). Serum follicular stimulating hormone was median 1 IU/l (range 1-11) in implant group (equivalent to premenopausal values) versus 43 (4-94) IU/l in oral group (p less than 0.01) and 72 (28-99) IU/l in controls (p less than 0.01). CONCLUSIONS--Subcutaneous oestrogen is more effective than oral oestrogen in preventing osteoporosis, probably owing to the more physiological (premenopausal) serum oestradiol concentrations achieved. It also avoids problems of compliance that occur with oral treatment.     

The therapeutic use of androgens in women

Androgens have significant and varied actions in women and there is now acknowledgment that women may experience symptoms secondary to androgen deficiency. There is also substantial evidence that prudent androgen replacement can be effective in relieving both the physical and psychological symptoms of androgen insufficiency, and is indicated for clinically affected women. Testosterone replacement for women is now available in a variety of formulations. It appears to be safe, with the caveat that doses are restricted to the ‘therapeutic’ window for androgen replacement in women, such that the beneficial effects on wellbeing and quality of life are achieved without incurring undesirable virilizing side effects.

The predominant symptom of women with androgen deficiency is loss of sexual desire. This is not limited to women experiencing a surgical menopause but may also be a feature of women who have either undergone premature or natural menopause. There is increasing interest in other uses of androgen replacement in women that include premenopausal iatrogenic androgen deficiency states, glucocorticosteroid-induced bone loss, management of wasting syndromes and possibly premenopausal bone loss, premenopausal loss of libido and the treatment of the premenstrual syndrome.