Modulation of gender-specific effects upon swim analgesia in gonadectomized rats

Gender-specific effects have been observed for continuous and intermittent cold-water swim (CCWS and ICWS respectively) analgesia: analgesic magnitudes following CCWS and ICWS are significantly smaller in female rats than in age-matched and weight-matched male rats. The present study evaluated the role of gonadal status in these gender-specific effects by examining CCWS and ICWS analgesia, hypothermia and activity in intact and gonadectomized rats. Following confirmation of the original gender-specific effects on the tail-flick and jump tests, it was found that both castration and ovariectomy significantly reduced CCWS and ICWS analgesia. Indeed, castrated males displayed similar magnitudes of analgesia as intact females. The more marked hypothermia observed in intact females indicated that this variable failed to account for the analgesic gender-specific effects. The reduced hypothermia following gonadectomy also failed to account for the analgesic changes. The increased activity during ICWS, but not CCWS following gonadectomy also did not account for the analgesic changes. These data suggest that gonadal steroids normally appear to facilitate these stress-related analgesic responses.     

Risks and benefits of steroid replacement therapy

The recommendations of the ESHRE workshop on ‘Risks andBenefits of Steroid Replacement Therapy’, held in Anacapri,September 18–19, 1987 ^*The workshop was sponsored by Schering (Italy).     

Psychiatric side effects of steroid therapy

Many psychiatric side effects have been noted with steroid administration. Occurring in about 6% of all patients on steroids, they are not uncommon. The English-language literature from 1951 to the present reveals numerous case reports and reviews but few prospective, controlled studies exploring this issue. This paper reviews the various psychiatric presentations and the relationship to patient profile, steroid type, dosage, and therapy duration. In 90% of cases, symptoms are reversible with steroid termination; some patients require psychopharmacologic treatment. Prophylaxis with lithium carbonate has met with good response in a few anecdotal reports and one prospective study.     

Tissue specificity: the clinical importance of steroid metabolites in hormone replacement therapy

Metabolic activations or inactivations of estrogens, progesterone and androgens are important steps towards the understanding of the physiological and the pathological effects of these hormones in the female organism. Analysis of the tissue specific metabolic pathways of sex steroids will result in a better understanding of successful hormone replacement therapy on the one hand and of the occurrence of steroid hormone related side effects on the other hand. In this contribution we analyse the different mechanisms involved in the synthesis of tissue specific metabolites and discuss the therapeutical importance of these metabolites in hormone replacement therapy.     

Postmenopausal hormone replacement therapy: endometrial and breast effects

The history of hormone replacement therapy (HRT) dates back to the late 1800s, when animal extracts of ovaries were first used. With the development of synthetic hormones, widespread use in postmenopausal women extended throughout the industrialized world, so that by the late 1900s roughly one-third to one-half of all postmenopausal women in the United States and Europe were taking HRT. Two events changed the course of use of HRT: the association of an increased rate of endometrial carcinoma with estrogen-only HRT and the association of an increased breast cancer rate with combined estrogen and progestin HRT. This review explores the evidence of the effects of HRT on the endometrium and the breast, with emphasis on the pathologic changes.     

Hyperprolactinemia and male sexual behavior: effects of steroid replacement with estrogen plus dihydrotestosterone

To determine if alterations in the availability of the active metabolites of testosterone (T) are involved in the inhibition of sexual activity in hyperprolactinemic animals, the effects of four ectopic pituitary grafts on copulatory behavior were examined in castrated male rats given subcutaneous implants of T or estradiol-17 beta (E2) plus 5 alpha-dihydrotestosterone (DHT). Two weeks after implantation of the steroid-filled capsules, half the animals of each group were given pituitary grafts and the remainder were sham-operated. Tests of copulatory behavior were performed prior to, and one, two, and three months following pituitary transplantation. Pituitary grafting caused significant inhibition of copulatory behavior in both T and E2 + DHT treated animals. PRL levels were significantly higher in E2 + DHT treated grafted males than in T treated grafted animals (2000 +/- 140 vs. 395 +/- 26 ng/ml), but did not differ between the corresponding control groups (61 +/- 8 vs. 73 +/- 6 ng/ml). The results of these experiments preclude the possible involvement of alterations in steroid secretion by the testes or modifications of the conversion of T to its active metabolites in the effects of hyperprolactinemia on copulatory behavior.     

Sex steroid replacement in post-menopausal women: effects on thyroid hormone status

We have measured serum thyroxine (T4), triidothyronine (T3), thyroid-stimulating hormone (TSH) free thyroxine (FT4) and thyroxine-binding globulin (TBG) levels in a total of 5 post-menopausal women who were receiving oestrogen alone (Premarin, n = 19), progestogen alone (Primolut-N, n = 12), a combination of oestrogen and progestogen (Prempak C, n = 14) or no treatment (control group, n = 12). No differences were observed between the Premarin and Prempak C groups; both exhibited elevated T4 and TBG levels, although free thyroxin (FT4) and T4/TBG concentrations were normal relative to those in the control group. The Primolut-N subjects showed subnormal T3 and FT4 levels relative to the controls. It was concluded that it is not possible to make general statements regarding the effects of sex steroids on FT4 levels.     

Gender differences in two forms of cold-water swim analgesia

Female rats display lower shock thresholds and less morphine analgesia than male rats, differences which are sensitive to gonadal manipulations. Baseline pain thresholds and morphine analgesia also vary across the estrous cycle of female rats. The first experiment demonstrated that 'nonopioid' continuous cold-water swim (CCWS: 2 degrees C for 3.5 min) analgesia and 'opioid' intermittent cold-water swim (ICWS: 2 degrees C, 18 10-sec swims and 10-sec rests over 3 min) analgesia are subject to gender-specific effects. The magnitudes of CCWS and ICWS analgesia were significantly lower in female rats as compared to either age-matched or weight-matched male rats. The jump test displayed a more consistent pattern than the tail-flick test. The second experiment failed to show differences in the magnitude of CCWS analgesia across the female estrous cycle. These data demonstrate that both opioid (ICWS) and nonopioid (CCWS) forms of stress-induced analgesia are sensitive to gender differences, and suggest that male gonadal hormones may enhance analgesic responsivity.     

Visual function in menopause: the role of hormone replacement therapy

OBJECTIVE: To assess the effects of hormone replacement therapy (HRT) on visual function after menopause. DESIGN: This study was conducted on 80 postmenopausal women aged 52 to 70 years. Women were randomly divided into two groups: 40 women were treated by oral HRT (equine conjugated estrogens 0.625 mg/day + dydrogesterone 5 mg/day in a continuous combined regimen), and 40 women were not treated with hormones (control group). Each woman underwent a contrast sensitivity test, a Schirmer test, and an evaluation of intraocular pressure before starting the study and 1 year after the beginning of the study. Statistical analysis was performed by Student's test and Fisher's exact test. RESULTS: Contrast sensitivity function was significantly improved in all spatial frequencies (1.5, 3, 6, and 12 cycles per degree) with the exception of 18 cycles per degree in the HRT group 1 year after the beginning of treatment, whereas the control group demonstrated significant impairment at the lowest spatial frequencies (1.5, 3, and 6 cycles per degree). Tear production was significantly improved in the HRT group 1 year after the beginning of treatment, and intraocular pressure was similar in the two groups before and after the beginning of the study. CONCLUSIONS: HRT improves visual function, promoting a better contrast sensitivity and a higher tear production, but does not modify intraocular pressure.     

Hormone replacement therapy and hemostasis: effects in Brazilian postmenopausal women

OBJECTIVE: To evaluate the impact that administration of transdermal estradiol gel combined with medroxyprogesterone acetate (MPA) has on hemostasis. METHODS: In this open prospective longitudinal study, thirty postmenopausal women received transdermal estradiol gel (1 mg/day) continuously combined with oral MPA (5 mg/day) for 12 days/month. The following parameters were determined: prothrombin time (PT), activated partial thromboplastin time (aPTT), factors VII, X, and XII activity, fibrinogen levels, thrombin-antithrombin complex levels, protein C and S antigen, antithrombin activity, plasminogen activator inhibitor type 1 (PAI-1) antigen, tissue-type plasminogen activator (t-PA) antigen, plasminogen activity and fibrin degradation products (FbDP) antigen. They were evaluated before and after 6 months of treatment. RESULTS: There was a significant decrease in factor VII activity (P=0.001), factor X activity (P=0.016), protein C antigen (P=0.022), antithrombin activity (P=0.025), plasminogen activity (P=0.023), t-PA antigen (P=0.043) and FbDP antigen (P=0.048) compared with baseline values. CONCLUSION: The results suggest that the treatment with transdermal estradiol gel combined with MPA avoids any major activation of coagulation and does not produce any overall effect on fibrinolysis. Therefore, this treatment might provide interesting effects on hemostasis in postmenopausal Brazilian women.     

Uterine receptivity in women receiving steroid replacement therapy for premature ovarian failure: ultrastructural and endocrinological parameters

Endometrial biopsies and plasma oestradiol (E2) and progesterone(P4) levels in 23 patients were evaluated during 26 replacementtherapy cycles for premature ovarian failure. Plasma E2 andP4 levels showed wide patient to patient variability, despiteeach patient being given the same hormone replacement therapy.Biopsies were studied by conventional histological dating andscanning electron microscopy (SEM). Eight morphological featuresof the surface epithelium that have previously been linked touterine receptivity for implantation were identified and quantified.No correlation was found between endometrial surface morphologyby SEM and circulation E2 and P4 levels. The results of thisstudy do not support the hypothesis that there is an obligatorylink between any of the eight morphological features measuredin this study and uterine receptivity for implatation. To date,three ongoing pregnancies have been achieved following 18 embryotransfers to a total of 10 of the women in the study group.     

Acoustic startle and open-field behavior in mice bred for magnitude of swim analgesia

Acoustic startle response (ASR) and open-field activity was examined in the 46th generation of mice that have been selectively bred for high analgesia (HA) and for low analgesia (LA) induced by 3-min swimming in 20°C water. These lines were earlier found to differ in brain opioid receptor density and in the expression of opioid-mediated phenomena, as analgesic sensitivity to opiates and reversibility of swim stress-induced analgesia (SSIA) by naloxone. For comparison, a randomly bred control (C) line was used. To measure the amplitude of ASR, the mice were exposed to 110-dB acoustic stimuli in a Coulbourn apparatus. In saline-injected mice, the ASR force was found significantly lower in the LA than in the HA, as well in the C line, but did not differ between the two last lines. Naltrexone hydrochloride (10 mg/kg IP 30 min before ASR testing) augmented the startle in the opioid receptor-dense HA line, but had no effect in the opioid receptor-deficient LA line, as well in the C line; therefore, the ASR magnitude in naltrexone-injected HA mice was significantly higher compared to the C line. HA mice displayed less activity in an open-field test; that is, they remained immobile longer in the center of the field, and thereafter performed less ambulation and less rearing against the wall compared to the LA line. Naltrexone failed to modify the open-field activity in any line. The results confirm that the pattern of ASR depends on the genetic makeup of the animals. The higher amplitude of ASR, taken together with the lower open-field activity of HA mice, can be interpreted in terms of higher anxiety level, compared to the LA line. It is suggested that the higher ASR in HA mice relies on a nonopioid mechanism, which is tonically inhibited by the opioid system.     

Transfer of pre-embryos donated and fertilized in vivo to recipients given a steroid replacement therapy

This study describes eleven procedures of non-surgical recoveryof preimplantation conceptuses from the uteri of eight fertiledonor women and the transfer of the recovered pre-embryos intothe uteri of infertile recipients with primary ovarian fallure,or with hypothalamic-pituitary failure. Conjugated oestrogensand progesterone were administered to recipients as replacementsteroids during the first 20 weeks of pregnancy, in order toproduce a secretory endometrium allowing nidation and developmentof the transferred conceptuses. Five pre-embryo transfers resultedin two viable pregnancies and one early abortion. Non-surgicalpre-embryo transfer is a simple and practical method for providingdonated ova to women lacking efficient ovarian function.     

Gonadal hormones and body temperature in rats: effects of estrous cycles, castration and steroid replacement.

The effects of estrous cycles, castration, subcutaneous steroid replacement, and intracranial steroid implants on the colonic temperatures were examined in 3 experiments. In Experiment 1 a rise in colonic temperature was observed at proestrus in intact females, and castration lowered the colonic temperatures of both males and females 1–2 hr before lights out. In Experiment 2 we tested the effects of 3 doses of progesterone and estradiol benzoate on the colonic temperatures of ovariectomized rats. Both hormones raised colonic temperature. The rise in colonic temperature was directly related to the progesterone dose, but it was inversely related to the dose of estradiol benzoate. In Experiment 3, progesterone and estradiol benzoate were implanted in the preoptic area of ovariectomized rats. Although estradiol benzoate in this site had no effect on colonic temperature, there was some suggestion that progesterone may increase colonic temperature when implanted in the preoptic area.     

The role of hormone replacement therapy in endometrial polyp formation

OBJECTIVE: To evaluate the iatrogenic effect of different protocols of hormone replacement therapy (HRT) on endometrial polyp formation adjusting for the confounding effects of other factors such as age, parity, weight and menopausal status at menopause. METHODS: Out of 2685 menopause patients 375 (13.9%) eligible patients were enrolled. Patients were randomized to three HRT types and three equal groups were formed. The first group received Premelle 2.5 mg (Group-I) (0.625 mg conjugated estrogen + 2.5 mg medroxyprogestorone), the second received Kliogest (Group-II) (2 mg estradiol + 1 mg norethisterone) and the last received Livial (Group-III) (2.5 mg tibolone) at least for 36 months without giving a break. After the first 18 months patients had their first office hysteroscopy and it was repeated in every 6 months until the end of third year to find out new and recurrent endometrial polyps. RESULTS: Multiple regression analysis revealed that the type of HRT, late menopause and obesity increased the occurrence of endometrial polyps. In Group-I five polyps, in Group-II ten polyps and in Group-III two polyps were detected. There were significant differences between G-II and G-I and G-II and G-III (P < 0.05), but there was no significant difference between G-I and G-III (P > 0.05). 82.3% of the polyps were detected in the third and fourth hysteroscopic examinations. Endometrial polyp recurrence was encountered in 4 (23.5%) patients, 1 in G-I and 3 in G-II without a significant difference (P > 0.05). No malignancy was detected in any of the specimen. CONCLUSION: We observed that endometrial polyp formation may be dependent on the type and dosage of the estrogen and progestogen. Especially a progestogen with high antiestrogenic activity may play an important preventive role in the development of endometrial polyps.     

Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on cardiovascular risk factors

OBJECTIVE: To determine the effects of oral and transdermal hormone replacement therapy on lipid profile and hemostatic factors in postmenopausal women. DESIGN: Twenty subjects were treated with oral E2 valerate (2 mg) combined with cyproterone acetate (1 mg) (group I) and 21 with transdermal E2 (1.5 mg) plus oral medroxyprogesterone acetate (5 mg) (group II). The effects on lipid profile and hemostatic parameters were evaluated at baseline and after 3, 6, and 12 months of treatment. RESULTS: Group I showed a stronger increase of high-density lipoprotein (HDL) cholesterol levels (2-8%) and stronger reduction of atherogenic indices (total cholesterol/HDL cholesterol and low-density lipoprotein/HDL cholesterol) than group II. Group II showed a more pronounced reduction of triglyceride (21-31%) and factor VII (6-10%) levels than group I. Both groups showed reduced concentrations of total cholesterol, low-density lipoprotein cholesterol, tissue plasminogen activator, plasminogen activator inhibitor-1, antithrombin III, and protein S, whereas protein C was increased after 12 months of treatment. CONCLUSIONS: The cardioprotective effects of hormone replacement therapy are demonstrated by favorable effects on lipid profile and fibrinolytic activity. Oral hormone replacement therapy showed a more prominent effect on lipoprotein metabolism than did transdermal administration, but transdermal medication had a stronger effect on triglyceride and coagulation factors. However, it needs to be considered that there is an increased risk of venous thrombotic events in the first year of treatment.     

Sleep in menopause: differential effects of two forms of hormone replacement therapy

OBJECTIVES: The aim of the present study was to evaluate differences between two regimens of estrogen/progestogen replacement therapy on nocturnal sleep in postmenopausal women. METHODS: Twenty-one (21) postmenopausal women were studied. They were randomized into two treatment groups: (1) estrogen (Premarin 0.625 mg) and medroxyprogesterone acetate (Provera 5 mg) (n = 11) or (2) estrogen (Premarin 0.625 mg) and oral micronized progesterone (Prometrium 200 mg) (n = 10). Postmenopausal women were recorded for two consecutive nights in the sleep laboratory at baseline and again after 6 months of treatment in a randomized trial. The women also had to fill out evening and morning sleep and vigilance questionnaires for 7 days before baseline recordings and for 23 days before month 6 recordings. RESULTS: Sleep efficiency was found to be significantly improved in the micronized progesterone group. It increased by 8% (p = 0.014) with no such increase observed in the medroxyprogesterone acetate group. Time spent awake after sleep onset was also significantly improved in the micronized progesterone group but not in the medroxyprogesterone acetate group. On the other hand, menopausal symptoms and subjective measures of sleep (questionnaires) improved in both groups after treatment. CONCLUSION: This study suggests that medroxyprogesterone acetate and micronized progesterone are both effective for treating menopausal symptoms but that the latter might better improve the quality of sleep in postmenopausal women taking estrogen.     

The relative effects of progesterone and progestins in hormone replacement therapy

Hormone replacement therapy (HRT) was initially given to protect women against osteoporosis and alleviate menopausal symptoms, such as hot flashes, depression, sleep disturbances, and vaginal dryness. In view of the understanding of oestrogen deficiency as a major trigger for the acceleration of cardiovascular risk after menopause, HRT may also be proposed as a substantial beneficial cardioprotective agent. Progestins, which may be added to oestrogen in combined HRT to reduce the risk of uterine malignancy, have a number of potential adverse effects on the cardiovascular system which could even attenuate the benefit of unopposed oestrogen replacement therapy in post-menopausal women.     

Pompe disease in adulthood: effects of antibody formation on enzyme replacement therapy

PurposeTo determine the effect of antibodies against recombinant human acid α-glucosidase (rhGAA) on treatment efficacy and safety, and to test whether the GAA genotype is involved in antibody formation.MethodsWe used enzyme-linked immunosorbent assay (ELISA) to determine anti-rhGAA antibody titers at baseline and at 6, 12, and 36 months of rhGAA treatment. We measured the capacity of antibodies to neutralize rhGAA enzymatic activity or cellular uptake and the effects on infusion-associated reactions (IARs), muscle strength, and pulmonary function.ResultsOf 73 patients, 45 developed antibodies. Maximal titers were high (≥1:31,250) in 22% of patients, intermediate (1:1,250–1:31,250) in 40%, and none or low (0–1:1,250) in 38%. The common IVS1/delex18 GAA genotype was absent only in the high-titer group. The height of the titer positively correlated with the occurrence and number of IARs (P ≤ 0.001). On the group level, antibody titers did not correlate with treatment efficacy. Eight patients (11%) developed very high maximal titers (≥156,250), but only one patient showed high sustained neutralizing antibodies that probably interfered with treatment efficacy.ConclusionsIn adults with Pompe disease, antibody formation does not interfere with rhGAA efficacy in the majority of patients, is associated with IARs, and may be attenuated by the IVS1/delex18 GAA genotype.