Optimizing continuous-combined hormone replacement therapy for postmenopausal women: a comparison of six different treatment regimens

OBJECTIVE: We sought to determine the optimum estradiol valerate-medroxyprogesterone acetate regimens for efficacy and safety. STUDY DESIGN: We performed a 24-month, randomized, double-blind phase II study. Four hundred nineteen women who were postmenopausal for at least 3 years were placed in six parallel treatment groups and received 1 or 2 mg estradiol valerate with either 2.5 or 5 mg medroxyprogesterone acetate. In two groups the dose of estradiol valerate was increased from 1 to 2 mg estradiol valerate after 6 months. RESULTS: A marked improvement of climacteric symptoms was observed, and most women had no bleeding even during the first 3 months of treatment. The best bleeding pattern was achieved with 1 mg estradiol valerate and 2.5 or 5 mg medroxyprogesterone acetate, and in most groups the bleeding pattern improved over time. No cases of hyperplasia were observed. CONCLUSION: All regimens alleviated climacteric symptoms and provided excellent bleeding control, even during the early weeks of treatment. A choice of various dose combinations offers flexibility of dosing, thus enabling therapy to be tailored to the needs of individual women.     

Testosterone addition to estrogen therapy – Effects on inflammatory markers for cardiovascular disease

Objective.?To analyze the effects of testosterone addition to estrogen therapy in comparison with estrogen alone on cardiovascular risk factors in postmenopausal women.

Methods.?Fifty surgically postmenopausal women were included in this double-blind, placebo-controlled and randomized study to receive daily oral treatment with estradiol valerate 2?mg + placebo (E/P) or estradiol valerate 2?mg + testosterone undecanoate 40?mg (E/T) for 24 weeks and then switched to the other regimen for another 24 weeks. Sex hormones, High sensitivity CRP (hsCRP), Interleukin-6 (IL-6), Tissue necrosis factor (TNF)-α, Insulin-like growth factor binding globulin (IGFBP-1), vascular cell adhesion molecule (VCAM)- 1, and homocysteine were analyzed at baseline and after 6 and 12 months.

Results.?Estradiol and androgens increased as expected during the treatments. After 6 months of E/P, increases of hsCRP and IGFBP-1 and a decline of VCAM were recorded, whereas IL-6, TNF-α, and homocysteine were unchanged. When testosterone was added to estrogen, the increase of IGFBP-1 and decline in VCAM was similar as with estrogen treatment alone. However, testosterone addition counteracted the estrogen-induced rise in hsCRP but had no effects on IL-6, TNF-α, and homocysteine.

Conclusion.?Data suggest that testosterone addition to estrogen treatment in postmenopausal women has a modest influence on inflammatory markers and there were no apparent adverse effects. On the contrary, the estrogen-induced increase in hsCRP was suppressed.     

The effect of oral estriol succinate therapy on the endometrial morphology in postmenopausal women: the significance of fractionation of the dose

Postmenopausal women were given estriol succinate orally in a daily dose of 4 mg X 2 for 14 days or 4 mg X 2, 8 mg X 1 and 2 mg in the morning + 2 mg at noon + 4 mg in the evening for 4 wk. Each group consisted of 4 women. The effect of the estrogen treatment was estimated by the endometrial curettage samples taken both before and after the hormone treatment. The curettage samples were studied by both light and electron microscopy. The results showed that a treatment period of 4 wk was necessary to obtain any effect. When 8 mg of estriol succinate was given in a single dose only a slight effect was obtained on the endometrium but when the same dose was divided in 2 daily 4 mg parts, the endometrium showed clearly proliferative changes. Thus estriol is able to produce the same endometrial effect as estradiol. Ultrastructurally the hormone treatment caused an increase in the cytoplasm of the endometrial epithelial cells. Also, whorls of cytoplasmic microfilaments often appeared near the nucleus of the cells.     

Effects of a sequential combination of estradiol valerate and cyproterone acetate on the functional properties of the arterial wall in menopausal women

Several studies have shown that estrogen replacement therapy protects postmenopausal women against coronary artery disease. This protective effect has been ascribed to the hormone's effect on serum lipids, as well as a direct action on the vascular wall. Concurrent administration of a progestin to protect women from the risk of endometrial hyperplasia may alter the protective effects of estrogen. The aim of this study was to assess the evolution of the endothelial function in postmenopausal women given a sequential combination of oral 2 mg estradiol valerate for 11 days, followed by 2 mg estradiol valerate associated with 1 mg cyproterone acetate for ten days (Climène). Each 21-day sequence was followed by a seven-day treatment-free interval. The women received a three-month treatment course. Thirty-one healthy postmenopausal women participated in the study (median age: 51 years; range: 45-59 years). Flow-mediated dilatation (FMD), a reflection of endothelium-dependent vasomotor function, increased from 8.47% at baseline (range: 4.57-11.02%) to 9.64% (range: 7.07-13.12%) at the end of the first treatment cycle; i.e., a 15% increase over baseline (P < 0.0001). FMD further increased after three treatment cycles to 10.59% (range: 8.09-15.22%); i.e., a 28.6% increase over baseline (P < 0.0001). FMD at the end of the first combined sequence or after the 11 days of estradiol only were similar (delta = 0.25%; range: -2.31-5.81%; not significant). In conclusion, in postmenopausal women, a three-month sequential treatment combining estradiol valerate and estradiol valerate plus cyproterone acetate (Climène) has beneficial effects on endothelial function as demonstrated by the evolution of the FMD. There was no decrease in the effect of estradiol on FMD when cyproterone acetate was added to estradiol.     

Effect of estradiol valerate and levonorgestrel on vaginal health

OBJECTIVES: To evaluate the effect of the combined hormone replacement therapy (HRT) estradiol valerate/levonorgestrel on vaginal symptoms, vaginal health index, vaginal pH, and vaginal cytology. STUDY DESIGN: A prospective, open-label study involving 32 postmenopausal women was performed in Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. All the subjects received sequential oral estrogen-progestogen hormone replacement therapy, which contains 2 mg estradiol valerate and 0.15 mg levonorgestrel, for 6 months. The results in terms of vaginal health index, vaginal pH, and vaginal cytology before and after treatment were analyzed. RESULTS: The mean age of these postmenopausal women was 52.56 +/- 3.33 years (range: 46-60 years). The mean time since the last menstrual period was 3.41 +/- 2.95 years (range: 1-15 years). The vaginal health index, which indicates vaginal health by means of scores for vaginal moistness, vaginal fluid volume, vaginal elasticity, vaginal mucosa, and vaginal pH rose significantly in all the women. The mean vaginal pH became significantly lower. The vaginal cytology showed an estrogenic effect on the karyopyknotic index (KPI) and the maturation value (MV) after 3 and 6 months of treatment. CONCLUSION: During estradiol valerate and levonorgestrel treatment, there were demonstrable improvements in the objective signs of vaginal atrophy: atrophic vaginal epithelium became thicker and vaginal pH lower, and the morphology of the vaginal cells was better.     

Is 1 mg of estradiol valerate or 0.625 mg of conjugated estrogens sufficient for all women to prevent menopausal bone loss?

Bone mineral content was measured by dual photon absorptiometry in 35 women who needed estrogen replacement therapy but did not want the addition of progestogens because they did not want regular bleeding. A total of 23 women were treated with estradiol valerate 1 mg per day over a mean period of 3.7 years; 12 women received conjugated estrogens 0.625 mg per day over a mean period of 5.3 years. The mean values of bone mineral content in both groups did not change. In the women on estradiol valerate, 61% had a decrease, and in those on conjugated estrogens, 67% had a decrease in bone mineral content. However, the calculated decrease per year was within the limits of the intraindividual reproducibility of the measurements. A difference between two measurements with a decrease of > 1.0 g hydroxyapatite/year over a period of > 3 years is larger than the limits of the intraindividual reproducibility. A decrease in bone mineral content > 1.0 g hydroxyapatite/year over a mean period of 3.98 years, SD 0.35, was observed in six of 23 (26%) of the women on estradiol valerate with a mean decrease of 5.28 g hydroxyapatite, SD 0.97. Only one of 12 (8%) of the women on conjugated estrogens had a decrease of 6.1 g hydroxyapatite over a period of 5.2 years. Periodic measurement of bone mineral is recommended in women on estrogen replacement therapy with estradiol valerate 1 mg per day or conjugated estrogens 0.625 mg per day for prevention of postmenopausal bone loss.     

Behavior the lipid spectrum following complete ovariectomy and subsequent substitution with estradiol valerate or norethisterone acetate

In a prospective trial the effects of oophorectomy and following administration of estradiol valerate (2,0 mg/day) or norethisterone acetate (5,0 mg/day) on the blood lipids were investigated during the late postoophorectomy time. After complete ovarectomy 52 women (42-49 years old) were randomized in two groups and substituted with these steroids from the 7. to 12. month after operation. Before total estrogen excretion/24 h urine, serum levels of estradiol and testosterone and the maturation value were studied. The blood levels of total-, HDL- nnd LDL cholesterol and triglycerides were markedly higher 2 and 6 months after castration than before. Norethisterone acetate depressed transitorily the total cholesterol and longer the HDL cholesterol, the triglycerides were increased 6 months after administration. A long lasting norethisterone acetate substitution in postmenopausal women should be below 5 mg/day.     

Intrauterine release of levonorgestrel--a new way of adding progestogen in hormone replacement therapy.

Forty perimenopausal women with climacteric complaints were randomly allocated to one of two estrogen-progestogen regimens. One group was treated cyclically for 3-week periods with 2 mg of estradiol (E2) valerate; during the last 10 days 250 micrograms of levonorgestrel was added. Another group was given 2 mg of E2 valerate a day and had a 20-micrograms/24-hour levonorgestrel-releasing intrauterine device (IUD) inserted. The study period was 1 year. Climacteric symptoms, bleeding patterns, and endometrial histopathology were recorded during the study. Subjective symptoms were equally diminished in both groups. In the IUD group, bleeding disturbances were gradually reduced, and 15 of 18 women became amenorrheic after 12 months, compared with the group given cyclic treatment in which all women bled regularly. No endometrial proliferation was found in any woman after 12 months. Thus, intrauterine release of 20 micrograms of levonorgestrel per day, in combination with orally administered E2, prevented endometrial proliferation and reduced uterine bleeding. This new approach to continuous combined hormone replacement therapy may be a well-tolerated treatment alternative in perimenopausal women.     

The effects of systemic hormonal replacement therapy on the skin of postmenopausal women.

OBJECTIVE: The aim of this study was to determine the effects of hormonal replacement therapy on the skin of postmenopausal women. METHOD: Forty-one postmenopausal women were randomly allocated to receive either hormonal replacement (valerate estradiol--2 mg/day for 21 days and cyproterone acetate--1 mg/day for 10 days) or placebo, both in a cyclic scheme for 6 months. Neither patients nor investigators were aware of the group allocation. Histologic changes were evaluated by skin biopsy of the left upper arm at baseline and after 6 months of treatment, utilizing computerized image analysis to assess the ratio area of epidermis/basement membrane length (AE/BML), ratio area of keratin/basement membrane length (AK/BML) and collagen and elastic fibers content. RESULT: Collagen content of the left upper arm increased after 6 months of treatment only in the hormonal group (+6.49%; P < 0.05). Other parameters did not present any significant alteration after treatment in both groups. CONCLUSION: Hormonal replacement for climacterics increases skin collagen content.     

Effects of simultaneous treatment with estrogen and testosterone on the uterus of female adult rats

BACKGROUND: Testosterone (T) associated with estrogen (E) has been used in hormonal replacement therapy in postmenopause women and the effects of this hormonal association on the uterus are not known. OBJECTIVE: To study the effect of long-term simultaneous exposure to testosterone and estrogen on the uterus of non-castrated adult female rats. METHODS: Groups of ten adult noncastrated female Wistar rats were treated with non-esterified testosterone and beta estradiol (subcutaneous implants with 50 mg of each hormone) or with testosterone cipionate and estradiol valerate (weekly intramuscularly or by subcutaneous injection of respectively, 2.85 mg/kg and 0.166 mg/kg). Control groups received no treatment (10 rats) or injections of diluents (6 rats). All animals were killed six months after hormonal exposure. RESULTS: All rats treated with T+E developed hyperplasia and hyperkeratosis of the vaginal and cervical epithelium and focal metaplasia with keratinization of the endocervical and endometrial epithelium. Ascending pelvic inflammatory disease with pyometra and tuboovarian abscesses were frequent (25% mortality until the end of the experiment). CONCLUSIONS: Testosterone associated with estrogen induced metaplasia of the genital epithelium but did not induce neoplastic lesions. The metaplasic lesions reduced the mucosal defense mechanisms enhancing ascending genital inflammatory disease. Although metaplasia of the cervical and endometrial epithelium has been observed after estrogen exposure in rats, testosterone does not appear to inhibit these estrogen effects.     

Comparison Of Cimicifuga foetida extract and different hormone therapies regarding in causing breast pain in early postmenopausal women

This study aimed to compare the influence between Cimicifuga foetida extract and different hormone therapies on breast pain in early postmenopausal women. A prospective, randomized, controlled clinical trial was conducted among 96 early postmenopausal women. Participants were randomly assigned to three groups: group A received 1?mg/day estradiol valerate plus 4?mg/day medroxyprogesterone acetate on days 19–30; group B received 1?mg/day estradiol valerate plus 100?mg/day micronized progesterone on days 19–30; group C received C. foetida extract, 1talet (contains 33.3?mg extract), t.i.d. Breast pain diary and numerical rating scale was used to access the breast pain. For 6 months’ treatment, the total incidence of breast pain in group A and B was significantly higher than that in group C (p?<?.05). The duration (day) of breast pain in each month decreased over time in group A and B while it was continuously low and without significant change in group C (p?>?.05). The intensity of breast pain was mild in most participants and did not differ among three groups (p?>?.05). During treatment of early postmenopausal women with C. foetida extract for 6 months, the incidence and duration of breast pain were lower than upon treatment with E2 plus cyclic MPA or m-P and did not change over time.     

Plasma lipid and lipoprotein effects of transdermal administration of estradiol and estradiol/norethisterone acetate.

To evaluate the effect of transdermal sequential treatment with estradiol and estradiol/norethisterone acetate on lipoprotein metabolism, 25 postmenopausal women received treatment for 12 cycles of 4 weeks each (2 weeks estradiol 50 micrograms/day and 2 weeks a combined patch delivering norethisterone acetate 0.25 mg/day and estradiol 50 micrograms/day). Blood samples for lipoprotein analyses were drawn before treatment and in estrogen and combined phases in cycles 3 and 12. Plasma total cholesterol, low (LDL) and high (HDL) density lipoprotein were all significantly reduced in both estrogen and combined phases. Eighteen of the women continued the treatment for 36 cycles. In this group the HDL-cholesterol had returned to baseline values in combined phase in cycle 24. Plasma cholesterol and LDL-cholesterol values remained significantly reduced throughout the whole study compared to the pre-trial values. The present study by transdermal sequential hormonal treatment results in a lipid and lipoprotein pattern with reduced total cholesterol and LDL cholesterol in postmenopausal women.     

Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol]

OBJECTIVE: The aim of this randomized cross-over study was the comparison between a sequential 28-day hormone replacement therapy (HRT) using micronized estradiol and a cyclic 21-day HRT using estradiol valerate with regard to the pharmacokinetics of estradiol. - MATERIAL AND METHODS: Fifty postmenopausal women were randomly assigned to be treated either with Trisequens(R) for 28 days or with Sisare(R) for 21 days. After a wash-out cycle, the women were treated for one cycle with the other preparation in a cross-over fashion. The pharmacokinetic profile of the serum concentrations of estradiol was measured on day 1, 21 and 28 each immediately before and 1, 2, 4, 6, 8, and 10 hours after intake of a tablet, and the AUC (area under the curve) was calculated. - RESULTS: The serum concentrations of estradiol increased from a mean of 10 pg/ml up to 40 pg/ml (Trisequens(R)) and 30 pg/ml (Sisare(R)) on day 1, and to 80 pg/ml (Trisequens(R)) and 60 pg/ml (Sisare(R)) on day 21, and declined to 40 pg/ml (Trisequens(R)) and 10 pg/ml (Sisare(R)) on day 28. The AUC as calculated from both treatment cycles, was significantly higher on day 1, 21, and 28 during treatment with Trisequens(R) than with Sisare(R). This difference was, however, not signifcant on day 1 and 21 of the first treatment cycle. - CONCLUSION: During treatment with 2 mg micronized estradiol the serum concentrations are significantly higher than with 2 mg estradiol valerate. On day 28 of treatment with Sisare(R), the estradiol levels decline to baseline values, while using Trisequens(R) they remain in the range of those measured on day 1.     

Effects of combined estrogen/testosterone therapy on bone and body composition in oophorectomized women

Objective.?To evaluate the effect of adding testosterone undecanoate 40?mg daily to estrogen therapy on bone markers, bone mineral density and body composition in oophorectomized women.

Methods.?Fifty women, 45–60 years old, who had undergone a hysterectomy and bilateral salpingo-oophorectomy for benign disorders, were randomly assigned to oral treatment with testosterone undecanoate 40?mg plus estradiol valerate 2?mg daily or placebo plus estradiol valerate 2?mg daily. Twenty-four weeks later, cross-over was performed to the other treatment regimen. Forty-four women completed the study. Their serum concentrations of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, osteocalcin, carboxyterminal telopeptide aminoterminal (ICTP), of type I collagen propeptide of type I procollagen (PICP) and interleukin (IL)-1 receptor antagonist were measured at baseline and after 24 weeks of both treatments, as were also their body mass index (BMI) and blood pressure. Bone mineral density of the total body, spine and hip and total body fat, total lean body mass, trunk fat and trunk lean mass were determined by dual-energy X-ray absorptiometry measurements at baseline and after 24 weeks of both regimens.

Results.?During treatment, the addition of testosterone counteracted the decrease in IGF-I and PICP seen with estrogen therapy alone. Osteocalcin and ICTP were significantly reduced to the same extent by both therapies. No change ocurred in the IL-1 receptor antagonist. A significant increase was seen in total lean body mass with the estrogen/testosterone regimen, but the total fat mass, trunk lean or fat mass remained unchanged after 24 weeks of both treatments. No effect was detected on total, hip or spinal bone mineral density after treatment with estrogen alone or estrogen/testosterone. Likewise, BMI and blood pressure were unaffected.

Conclusions.?The addition of testosterone to oral estrogen might have positive effects on bone as suggested by the fact that it counteracted the decline in IGF-I and PICP levels. An anabolic effect on muscle was reflected by an increase in the total lean body mass. No adverse effects were noted on BMI, fat distribution or blood pressure during the 6-month treatment with oral testosterone undecanoate.     

Serum testosterone, FSH/LH and urinary excretion of estrogens and corticoids during treatment with an injectable, longacting estrogen-DHEA preparation.

Ten weeks after total hysterectomy and bilateral salpingo-oophorectomy, nine women were treated with injections of Gynodian, composed of 4 mg estradiol valerate and 200 mg dehydroepiandrosterone enanthate, followed by injections of Primodian, composed of 4 mg estradiol valerate and 90.27 mg testosterone enanthate. Before commencement of treatment estimation of serum FSH, LH and testosterone, and analyses for total estrogen, 17-ketogenic steroids and fractionated 17-ketosteroids in 24-hour urine samples were carried out in all patients. The same serum and urine analyses were made 2 weeks after the first Gynodian injection and the first Primodian injection respectively. Serum testosterone concentrations did not change during treatment with Gynodian, whereas they rose markedly after administration of Primodian. Two weeks after the first injection of Gynodian and also of Primodian, the total estrogen excretion was only slightly increased in comparison with the value measured before start of treatment, and the serum FSH/LH ratio was only slightly depressed. The daily urinary excretion of 17-ketogenic steroids and of fractionated 17-ketosteroids were unchanged during treatment.     

When applied to facial skin,does estrogen ointment have systemic effects?

Summary We examined cytological vaginal smears of 17 women before and after three months of dermal estrogen (1 g of 0.01% estradiol ointment or 0.3% estriol ointment once daily), applied to the face for dermatological indications. The mean age was 57.1±7.6 years (range from 46 to 66). Seven women had estrogenic smears (more than 10% superficial cells) before therapy. Nine women were treated with 0.01% estradiol ointment and 8 were treated with 0.3% estriol ointment. Both groups had gynecological examinations including cervical and vaginal smears before and after treatment and also monthly measurements of serum follicle-stimulating hormone, prolactin and estradiol levels. Serum hormone levels and the appearance of vaginal smears showed no significant change during treatment.     

The effects of hormone therapy, estrogen therapy and tibolone on apoptosis and cyclin D1 expression in postmenopausal vaginal epithelium

OBJECTIVE: To investigate the effects of hormone therapy, estrogen therapy and tibolone on markers of apoptosis including bcl-2, and bax and cyclin D(1) expression in postmenopausal vaginal epithelium. STUDY DESIGN: Thirty postmenopausal women were randomized to the treatment protocols (0.625 mg conjugated equine estrogen (CEE) + 2.5 mg medroxyprogesterone acetate (MPA); 2mg estradiol valerate; 2.5mg tibolone). After baseline vaginal biopsy, control biopsies were performed after 70 days following the initiation of the therapy. Bcl-2, bax, Bcl-2/bax ratio, cyclin D(1) measurements were performed immunohistochemically. Data were analyzed by Kruskal-Wallis, Mann-Whitney U and Wilcoxon tests. RESULTS: After the treatment period the above-mentioned parameters were not different among the groups except for cyclin D(1) levels. Cyclin D(1) expression was found to be strong in patients with treated estradiol valerate. CONCLUSIONS: The effects of estrogen on cyclin D(1) expression were not detected with tibolone or with the addition of progesterone to estrogen in the vaginal epithelium. Cyclin D(1) appeared to have stronger effects on the estrogen related proliferation compared to apoptotic markers in vaginal epithelial cells.     

The effect of estradiol valerate and dienogest combination on serum homocysteine levels in postmenopausal women: a clinical trial.

Several studies have verified that hormone replacement therapy (HRT) has protective effects on postmenopausal women's cardiovascular condition. However, highly significant recent studies have reported that women treated with HRT have more cardiovascular events than untreated women. An elevated homocysteine level is one important risk factor for cardiovascular disease (CVD). As a good indicator of CVD risk, we examined the changes in plasma homocysteine levels of postmenopausal women treated with HRT. In our study, we administered estradiol valerate (2 mg) and dionegest (2 mg) to 34 postmenopausal women recruited randomly from our menopause clinic, and measured plasma homocysteine levels of patients at baseline and after 3 and 6 months of therapy. The changes in plasma homocysteine levels of treated patients were not statistically significant (p = 0.241). Our results indicate that 6 months of estradiol valerate and dionegest therapy does not change homocysteine levels in postmenopausal women.     

Sequentially combined estradiol valerate plus levonorgestrel therapy decreases 18:1 trans-fatty acid content of plasma lipids in healthy postmenopausal women.

Trans-fatty acids (TFA) have been classified as atherogenic dietary constituents but the effect of hormone replacement therapy (HRT) on their concentrations is not known. We used a washout protocol to study the effect of long-term estrogen and combined estrogen-progestin HRT on plasma elaidate (18:1t), which is the trans isomer of oleate and the major TFA in the diet. The study group comprised 15 women receiving estradiol valerate HRT and 15 women receiving combined HRT with estradiol valerate and levonorgestrel. The concentrations of elaidate in plasma phospholipids, cholesteryl esters and triglycerides were determined by gas chromatography. At baseline, the total plasma elaidate concentration was lower in the combined HRT group than in the estradiol valerate HRT group (p < 0.01). In the combined HRT group, the concentration of elaidate increased significantly after withdrawal of HRT (p < 0.001) and decreased again to the baseline level after restart of therapy (p < 0.001). These changes were due to decreases in the concentrations of phospholipids and triglycerides; in phospholipids there was also a proportional decrease of elaidate. There were no changes in elaidate in women receiving estradiol valerate alone. Our results suggest that long-term combined HRT treatment decreases plasma TFA, which is not achieved by estrogen alone.     

The effect of 2 mg estradiol-17 beta plus 1 mg estriol, sequentially combined with 1 mg norethisteroneacetate, on LH, FSH, estradiol-17 beta, progesterone, testosterone and prolactin after ovariectomy

The object of the study was to see whether maintenance of serum estradiol levels corresponding to the early and mid-follicular phase can prevent the gonadotrophin increase following ovariectomy. We also wanted to study the effect on LH and FSH of an additional dose of 1 mg dose of 1 mg norethisterone acetate administered for 10 days during each month. In 22 women with normal cycles 1 mg of estradiol benzoate was injected i.m. at the time of ovariectomy. From the first post-operative day onwards they received daily doses of 2 mg estradiol and 1 mg estriol in the form of micronized tablets. From the 41st to the 50th day and again from the 69th to the 78th day the patients received additional daily doses of 1 mg norethisterone acetate. LH, FSH, estradiol-17 beta, (E2) progesterone (P), testosterone (T), and prolactin (PRL) were measured in intervals of 2-17 days. Even though the estradiol mean values remained constant in the range of 65-115 pg throughout the period under observation, the LH mean levels increased continuously from 8 to a maximum of 23.9 mU/ml, and the FSH mean level from a pre-operative value of 6-48.0 mU/ml on the 85th day. On the 7th day after the last administration of norethisterone acetate LH was slightly depressed while FSH continued to rise slightly. Both FSH and LH are negatively correlated with E2 and this inverse correlation becomes even more pronounced the more time has elapsed after surgery. These findings suggest that not only the estrogens inhibit FSH and LH but also other steroids and/or nonsteroidal ovarian inhibiting factors.