Search PubMed⌕ Search

Biomedical subjects

H L Judd

Publications and source records attributed to H L Judd.

At least 73 records · Page 4Linked to original sources
PubMed1987

Nonoral routes of estrogen administration.

Thus, the effects that a specific estrogen has on the liver is the summation of several mechanisms, including the first pass mechanism and the enhanced delivery of circulating estrogens to this organ. For example, the major estrogen in conjugated estrogen is estrone sulfate. Based on the present data, very little circulating estrone sulfate is available to the brain or uterus (Fig. 25). Since most of the hypothalamus is behind the blood-brain barrier, it is unlikely estrone sulfate exerts a direct action on gonadotropin-releasing hormone (GnRH) neurons to reduce its secretion and, subsequently, gonadotropin levels. Estrone sulfate also does not interact with the estrogen receptor. It is possible the small amount of estrone sulfate that crosses the blood-brain barrier is converted to unconjugated estrogens locally and these could have function. More likely, the major mechanism by which estrone sulfate suppresses GnRH release is through conversion to unconjugated estrogens, principally estrone, in the liver. The large extraction of estrone sulfate by the liver allows accessibility of the hepatocyte for this conversion. Based on this concept, conjugated estrogen must enter the liver to be converted to its active forms. The route of administration then should have little impact on changing the relative potency of this preparation on hepatic and nonhepatic markers of estrogen action. For ethinyl estradiol, the preparation is orally active because it is rapidly and almost completely absorbed from the stomach and undergoes limited hepatic metabolism before entry into the general circulation (Fig. 26). This limited hepatic metabolism reduces the impact of the first pass mechanism on ethinyl estradiol. Thus, the enhanced hepatic action of ethinyl estradiol is principally related to the greater entry of this estrogen into the liver than other organs (Fig. 27). Consequently, the route of administration should have little impact on the exaggerated hepatic actions of this estrogen. Orally administered estradiol undergoes substantial hepatic metabolism to less active forms, principally estrogen conjugates. The amount of estradiol leaving the liver following oral administration is substantially less than that which enters it through the portal vein. The systemic administration of estradiol avoids this initial hepatic metabolism. Furthermore, only 25 per cent of nonorally administered estrogen will go to the liver at each pass, and nonhepatic tissues would be exposed to a greater extent than after oral administration. Thus, peripheral administration of estradiol reduces the exaggerated hepatic responses in comparison to nonhepatic actions.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Cutaneous↗
PubMed1986

Biologic effects of transdermal estradiol.

We conducted a dose-response study in 23 postmenopausal women to compare the physiologic effects of transdermal estradiol and oral conjugated equine estrogens. The doses studied were 25, 50, 100, and 200 micrograms of transdermal estradiol per 24 hours, and 0.625 and 1.25 mg of oral conjugated estrogens. Transdermal estradiol increased circulating concentrations of estradiol and estrone. Oral conjugated estrogens also raised the levels of estrogen, particularly estrone. Both preparations lowered gonadotropin levels, decreased the percentages of vaginal parabasal cells, increased the percentage of superficial cells, and lowered urinary calcium excretion. The effects of 0.625 and 1.25 mg of oral estrogens were similar to those of 50 and 100 micrograms of transdermal estradiol per 24 hours, respectively. Oral estrogens significantly increased circulating levels of renin substrate, sex-hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin; transdermal estradiol had no effect. The higher dose of oral estrogens had favorable effects on concentrations of low-density and high-density lipoproteins, but transdermal estradiol did not. Neither preparation affected any of the four clotting factors studied. These data indicate that transdermal estradiol can elicit many of the desirable actions of estrogen while avoiding the pharmacologic effects of oral estrogens on hepatic proteins.

Administration, Oral↗
PubMed1986

Treatment of severe androgen excess due to ovarian hyperthecosis with a long-acting gonadotropin-releasing hormone agonist.

A 31-year-old nulligravid patient presented with irregular menses, severe hirsutism, and infertility. Evaluation revealed marked increases of serum androstenedione and testosterone levels and a possible ovarian mass. At operation a cystic teratoma was removed from the left ovary and bilateral wedge resection revealed severe ovarian hyperthecosis. After operation only a transient decrease of androstenedione and testosterone was noted and the patient failed to ovulate or improve clinically. Subsequently a long-acting gonadotropin-releasing hormone agonist was administered daily for 6 months, which reduced circulating delta 4-steroids and estrogens to levels approximating those of castrated women. Immediately after discontinuation of treatment, ovulation induction was successfully achieved with human menopausal gonadotropin. This report introduces a new therapeutic approach to the problem of severe ovarian hyperthecosis and may provide an opportunity for childbearing in these patients.

Adult↗
PubMed1986

Danazol inhibits steroidogenesis by the human ovary in vivo.

Gonadotropins, estradiol (E2), and the steroid precursors of ovarian estrogen secretion were examined in women on danazol to clarify actions of the medication on hypothalamic-pituitary-ovarian function. Follicle-stimulating hormone was not altered acutely after a single maximal dose or chronically during therapy, whereas a slight but significant increase in luteinizing hormone was noted during the 6 months of treatment. During danazol treatment, there was a blunted response of E2 to injections of human menopausal gonadotropins. The progestin and androgen precursors of E2 were reduced, with the exception of 17-hydroxypregnenolone, which was significantly increased. This 17-hydroxylase enzyme block persisted in spite of dexamethasone suppression of adrenal function. Therefore, the reduced ovarian secretion of E2 in women receiving danazol is due in part to reductions of ovarian precursor steroids for E2 synthesis, consequent to a direct ovarian action of the medication.

Adult↗
PubMed1986

Chronological changes in fertility, fecundity and steroid hormone secretion during consecutive pregnancies in aging rats.

During aging in female rats the incidence of regular estrous cyclicity decreases progressively. Concomitant with this decrease are declines in both fertility and fecundity in aged females. The causes for these age-related losses in reproductive function are currently unknown. To reveal the biology and endocrinology of pregnancy in aging females, we performed a longitudinal study in a group of multiparous rats bred once every 2 mo. Beginning at 4 mo and continuing through 12 mo of age in the same individual females, we determined the chronological changes in estrous cyclicity and fertility; examined the number of implantation scars; estimated the fetal resorption rate; and assessed the patterns of progestin, androgen, and estrogen secretion during 5 consecutive gestations. During each pregnancy, blood samples were obtained from the mothers on Days 2, 5, 8, 11, 14, 16, and 19 for measurement of steroid hormone concentrations. Laparotomies were performed after parturition to count the number of implantation scars. To estimate the number of fetal resorptions, the difference between the number of implantation scars and the total number of pups delivered was calculated for each animal. Fertility during aging followed a similar but more dramatic pattern of decline than did the incidence of regular cyclicity. While almost all females became infertile when their regular ovulatory cycles ceased, an increasing proportion of middle-aged (10-12 mo of age) regularly cyclic rats also failed to reproduce successfully. These observations indicate that the loss of fertility in aging female rats is due largely, but not exclusively, to the cessation of regular ovulatory cycles. Beginning at 8 mo and continuing to 12 mo of age, a significant (p less than 0.01) decline in litter size was observed in these multiparous rats. This decline was associated with a similar decrease in the number of implantation scars. Neither the estimated number of fetal resorptions nor the number of dead pups delivered per pregnant rat changed significantly during 5 consecutive gestations. There were, however, age-related gradual increases in the percentage of fetal resorptions/implantation scars and of dead pups/total number of pups delivered. These data indicate that the age-related decline in fecundity is due mainly to reproductive failures early in gestation. The patterns of decreases in both fertility and fecundity found in repeatedly sampled and laparotomized females were similar to those seen in untreated multiparous rats.(ABSTRACT TRUNCATED AT 400 WORDS)

20-alpha-Dihydroprogesterone↗
PubMed1986

The relation of ovarian steroid levels in young female rats to subsequent estrous cyclicity and reproductive function during aging.

In multiparous rats, the incidence of regular estrous cyclicity and fertility decreases markedly at middle age. However, recent studies have shown that repeated pregnancies or progesterone (P) implants can subsequently cause retired breeder females to maintain regular cyclicity for an extended period of time; these results suggest a P-mediated deceleration of reproductive aging. In the present study, we examined the relation of ovarian steroid levels in young virgin females to their subsequent estrous cyclicity and reproductive function during aging as compared to multiparous females. Beginning at 4 mo of age and continuing to 6 mo of age, regularly cyclic virgin rats received either consecutive P implants (n = 41) or no implants (controls, n = 45) for 3 wk, followed by implant removal for 1 wk. Additional females (n = 72) were mated and allowed to undergo repeated pregnancies at 4, 6 1/2, and 8 mo of age. Blood samples were obtained throughout the estrous cycle (virgin females), during pregnancy (multiparous rats), and on Day 11 of successive treatments with P implants (virgins with P implants) for P, estradiol (E2), and testosterone (T) measurements. Subsequently, regularly cyclic females from all three groups were mated with fertile males to undergo term pregnancies at 10 and 12 mo of age. While the virgin controls showed cyclic increases in P, T, and E2 secretion during their estrous cycles, the P-implanted females had persistently low E2 and high P and T levels during treatment, which indicates an inhibition of ovarian E2 synthesis by P.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1986

Estrogen exposure affects the post-ovariectomy increases in both LH and FSH release in female rats.

In female rats ovariectomy (OVX) on the morning of diestrus day 2 resulted in a prompt (within 8 h) and gradual increase in LH release, whereas a similar operation on estrus did not raise serum LH until 24 h later. In proestrous females, OVX in the morning neither prevented the anticipated LH surge on that evening, nor increased LH release on the next morning. Since circulating concentrations of estradiol (E2) are progressively increased during diestrus day 2 and proestrus, this pattern of E2 secretion may affect the acute increase in LH secretion following OVX. To test such a hypothesis, we examined the effects of large, sustained or large, transient increases in circulating estrogen on the subsequent increase in gonadotropin secretion after OVX. On the morning of diestrus day 1 a subcutaneous injection of 20 micrograms estradiol benzoate (EB) produced prompt and large increases in both serum E2 and estrone (E1) for about 2 days, despite OVX of females at 24 h after the EB injection. An injection of 20 micrograms 17 beta-estradiol (E2) also promptly increased both serum E2 and E1. micrograms E2 injection were twice that observed after 20 micrograms EB, and both E2 and E1 returned to low baseline values within 24 h after the E2 injection. In contrast, administration of 1 microgram EB only produced small and transient rises in serum E2 and E1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Rates of bone loss in the appendicular and axial skeletons of women. Evidence of substantial vertebral bone loss before menopause.

We made longitudinal measurements of bone mineral density (BMD) in 139 normal women (ages 20-88 yr) at midradius (99% cortical bone) and lumbar spine (approximately 70% trabecular bone) by single- and dual-photon absorptiometry. BMD was measured 2-6 (median, 3) times over an interval of 0.8-3.4 yr (median, 2.1 yr). For midradius, BMD did not change (+0.48%/yr, NS) before menopause but decreased (-1.01%/yr, P less than 0.001) after menopause. For lumbar spine, there was significant bone loss both before (-1.32%/yr, P less than 0.001) and after (-0.97%/yr, P = 0.006) menopause; these rates did not differ significantly from each other. Our data show that before menopause little, if any, bone is lost from the appendicular skeleton but substantial amounts are lost from the axial skeleton. Thus, factors in addition to estrogen deficiency must contribute to pathogenesis of involutional osteoporosis in women because about half of overall vertebral bone loss occurs premenopausally.

Adult↗
PubMed1986

Enhanced hepatic extraction of estrogens used for replacement therapy.

Oral estrogen administration elicits greater effects on hepatic than on nonhepatic markers of estrogen action. This has important clinical implications, since the hepatic actions of estrogens are believed to account for several complications of this form of therapy. To date, the mechanism responsible has been attributed to the so-called first pass effect of the orally administered hormones. The present study was undertaken to examine the in vivo extraction from the circulation of all commercially available classes of estrogens used for replacement therapy. Influxes from the microcirculation into three important target organs of estrogen action, i.e. the brain, uterus, and liver, were assessed. This was accomplished by the use of previously described double isotope, single injection, timed tissue-sampling techniques. For the brain, two patterns of influx were found using different injection vehicles. The first was characterized by high extraction (80-100%) in the absence of plasma proteins. The only inhibitory effects on influx were exerted by plasma proteins. Estrogens displaying this pattern were estradiol, estrone, and ethinyl estradiol. The second pattern was characterized by very restricted influx in the absence of plasma proteins, and plasma protein binding had little or no additional effect. In the absence of plasma proteins, the percentages extracted of estrone sulfate (E1S) and diethylstilbestrol were 6.5% and 38.5%, respectively. For the uterus, the patterns of extraction of all five estrogens were similar to those found for the brain. In contrast, the hepatic microvasculature was freely permeable to all estrogens including E1S and diethylstilbestrol. Albumin binding had little or no effect on hepatic uptake. Significant reductions in the influx of estradiol and E1S were found only when the injection vehicle was human pregnancy serum (high sex hormone-binding globulin concentration). In the presence of plasma proteins, the hepatic extraction of all of the estrogens studied significantly exceeded that in the brain and uterus. We conclude that enhanced delivery of circulating estrogens to the liver compared to that to the brain and uterus provides a further explanation for the enhanced hepatic actions of these preparations when used for oral replacement therapy.

Animals↗
PubMed1986

The effect of bromocriptine on gonadotropin and steroid secretion in polycystic ovarian disease.

Use of bromocriptine in some women with polycystic ovarian disease (PCO) has resulted in ovulation induction, although a mechanism has not been established. The purpose of this study was to determine the effect of bromocriptine on gonadotropin and steroid secretion in this disorder. Two groups of seven patients were given bromocriptine at a dose of either 5 mg/day for 2 months or 10 mg/day for 1 month. Ten normal ovulatory women served as controls. In PCO patients, mean serum levels of LH, bioactive LH, androstenedione, testosterone, unbound testosterone, dehydroepiandrosterone sulfate (DHEA-S), and estrone were significantly greater (P less than 0.05) than those of normal women, whereas FSH, PRL, dihydrotestosterone, 3 alpha-androstanediol, and estradiol were not different. Assessment of gonadotropin secretion before and during treatment revealed that basal levels, episodic secretion, and responses to GnRH (25 micrograms, iv) were unaltered by either dose of bromocriptine. Of the remaining hormones, PRL and DHEA-S significantly decreased in response to both doses. There were no changes in the clinical status of patients during treatment. These findings indicate that in PCO patients with normal PRL levels, gonadotropin secretion is unaltered by bromocriptine therapy. The concomitant declines of PRL and DHEA-S confirm previous data reported for this syndrome and suggest a role for PRL in the production of adrenal androgens.

Androstenedione↗
PubMed1986

Serum bioavailability and tissue metabolism of testosterone and estradiol in rat salivary gland.

The concentration of testosterone in saliva is probably in equilibrium with the concentration of cellular exchangeable testosterone in salivary gland, and these pools are a function of hormone transplant from the plasma compartment, and hormone metabolism in salivary gland cells. Both of these processes were examined in the present study using the carotid injection technique in normal and pilocarpine-stimulated ketamine-anesthetized rats. Both testosterone and estradiol were rapidly transported across salivary gland capillaries in vivo from the circulating albumin-bound pool. Estradiol, but not testosterone, was also rapidly transported into salivary gland from the circulating human sex hormone-binding globulin-bound pool. Hormone transport was several-fold greater than the capillary transport of [3H]bovine albumin, indicating that bound hormone was available for transport across salivary gland capillaries via an enhanced dissociation mechanism, with the plasma protein primarily residing in the plasma compartment. This result was confirmed by thaw-mount autoradiography, which showed diffuse distribution of [3H]testosterone in salivary gland, but vascular retention of [3H]bovine albumin. The concentration of exchangeable cellular testosterone in rat saliva was less than 4% of the total or plasma exchangeable testosterone in the rat. This marked discrepancy between the concentration of plasma and cellular exchangeable hormone suggested that there was rapid metabolism of androgen by salivary gland in vivo. This was confirmed by chromatographic separation of [3H] testosterone and labeled metabolites in homogenates of salivary gland. By 60 sec after injection, approximately 30% of the radioactivity in the salivary gland was in the form of androgen metabolites, which primarily comigrated with an androstenedione standard. The data indicate that albumin-bound testosterone, albumin-bound estradiol, and sex hormone-binding globulin-bound estradiol are all exchangeable in salivary gland capillaries. The low concentration of cellular exchangeable testosterone in salivary gland appears to be due to rapid tissue metabolism of this hormone. Thus, changes in androgen metabolism may alter salivary gland hormone concentrations independent of any change in the concentration of biologically active hormone in plasma.

Adult↗
PubMed1986

Impotence in scleroderma.

Hormonal, neurologic, and vascular factors affecting potency were evaluated in 10 men with scleroderma and in 10 age-matched men with rheumatoid arthritis. Impotence was reported by 6 of the patients with scleroderma and none with rheumatoid arthritis. Studies of serum testosterone, free testosterone index, follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, thyroxine, and thyrotropin did not show a hormonal basis for impotence in any patient. Neurologic causes were not found on physical examination. Penile blood pressures were markedly abnormal in 4 impotent patients, intermediate in 2 impotent and 3 potent patients, and normal in 11 potent patients. A history of claudication and diminished ankle blood pressures indicated large vessel disease in 2 impotent patients; the remaining 4 impotent men had normal ankle pressures, suggesting that their poor penile blood pressures and impotence were due to small vessel disease, perhaps the small artery lesions of scleroderma.

Adult↗
PubMed1986

Higher maternal levels of free estradiol in first compared to second pregnancy: early gestational differences.

Serum samples drawn from 34 women in the early part of both their first and their second pregnancies were assayed for estradiol (E2), percentage of free E2, and sex hormone-binding globulin-binding capacity (SHBG-bc). Subjects were participants in the Collaborative Perinatal Study conducted by the National Institute of Neurological and Communicative Disorders and Stroke (Bethesda, MD) to evaluate factors related to adverse pregnancy outcome. All pregnancies were full term, and no offspring had a congenital malformation. After adjustment for week of pregnancy, the percentage of free E2 was 9% higher (two-sided P = .007) and the amount of free E2 was 17% higher (two-sided P = .03) in first-pregnancy sera. Total E2 was also 7% higher in first-pregnancy sera after adjustment for week of pregnancy; SHBG-bc was 7% lower after adjustment for week of pregnancy and 9% lower after simultaneous adjustment for week of pregnancy and weight at the start of pregnancy; but these differences were not statistically significant. These findings confirm our previously published hypothesis that the early part of a woman's first pregnancy differs endocrinologically from her second and may provide further insight into pregnancy-related risk factors for testis cancer and cryptorchidism and into the protection afforded by first full-term pregnancy against breast cancer.

Adult↗
PubMed1985

Do regular ovulatory cycles increase breast cancer risk?

The "estrogen window hypothesis" of the etiology of breast cancer proposes that unopposed estrogen stimulation is the most favorable state for tumor induction and that normal postovulation progesterone secretion reduces susceptibility. The authors believe that epidemiologic and experimental studies suggest rather that the opposite is true, i.e., that breast cancer risk is directly related to the cumulative number of regular ovulatory cycles. Unlike the endometrium, breast tissue mitotic activity is enhanced in the luteal phase of the menstrual cycle. Regular vigorous physical activity is one method of reducing the frequency of ovulatory cycles, and such exercise could markedly reduce a woman's lifetime risk of developing breast cancer.

Adolescent↗
PubMed1985

Acute ovarian responses to a long-acting agonist of gonadotropin-releasing hormone in ovulatory women and women with polycystic ovarian disease.

A long-acting agonist of gonadotropin-releasing hormone (GnRH-a, 100 micrograms/day) was administered daily for 14 days in four patients with polycystic ovarian disease (PCOD) and eight ovulatory women (OW) to determine acute hormone responses. Initiation of GnRH-a treatment in OW on day 5 of their menstrual cycles (OW-day 5) stimulated a greater acute rise of serum follicle-stimulating hormone (FSH) than that seen in OW beginning treatment on day 2 (OW-day 2) or PCOD patients. FSH levels fell to baseline values with repeated injections, whereas luteinizing hormone levels remained elevated in all patients. An acute rise and progressive fall of estradiol (E2) was found in all groups. The OW-day 5 group demonstrated a secondary increase, which by day 14 was clearly greater than that found in the other groups. This secondary increase of E2 in the OW-day 5 group was associated with lower abdominal pain, whereas OW-day 2 and PCOD patients were asymptomatic. For comparison, human menopausal gonadotropin (150 IU/day for 3 days) stimulated a significantly greater increase of E2 in OW-day 5 than in PCOD patients. These studies indicate that daily GnRH-a administration induced variable effects on ovarian function, which depended on when it was begun during the menstrual cycle and whether it was given to ovulatory or PCOD subjects. In addition, abdominal discomfort associated with GnRH-a use in regularly OW can be avoided by commencing agonist administration earlier in their menstrual cycles.

Abdomen↗
PubMed1985

Relation of circulating estradiol and progesterone to gonadotropin secretion and estrous cyclicity in aging female rats.

The progressive cessation of regular ovulatory function in aging female rats is preceded by a significant decrease in the magnitude of the proestrous LH surge during regular estrous cycles. However, our recent study has demonstrated that normal LH secretion and regular estrous cycles can be maintained for an extended period of time in aging females housed with fertile males and allowed to undergo repeated pregnancies. Since progesterone (P) secretion is persistently increased in pregnant rats, the present study examined whether repeated increases in circulating progesterone accounted for these results. Starting at 8 months of age and continuing to 13 months, multiparous rats were grouped and treated as follows: controls: females were housed five per cage; mated: five females were housed with one fertile male and allowed to undergo repeated pregnancies; and P-implanted: females were housed five per cage and implanted sc with Silastic capsules containing P for 3 of every 4 weeks. During the 4.5 months of study, serum concentrations of estradiol (E2) in the P-implanted rats remained between 13 and 27 pg/ml, similar to levels in pregnant females (8-26 pg/ml) of the mated group. These E2 values were less than the preovulatory increase in serum E2 on proestrus (mean +/- SE, 56 +/- 10 pg/ml) in cyclic control females. In contrast, serum P values were persistently elevated in both the pregnant and the P-implanted rats, although the values in the latter (27-55 ng/ml) were about one third to one half of those in the former group (117-125 ng/ ml). All treatments were stopped at 13 months of age, and estrous cycle patterns were determined thereafter. Between 13 and 17 months of age, the percentages of regularly cycling rats were significantly (P less than 0.01) greater in the mated group (50%, 36%, and 15% at 13, 15, and 17 months, respectively) than in the control group (23%, 20%, and 9%, respectively). During this same period, 50% of the females from the P-implanted group continued to display regular cycles. By the age of 11 months, 8 of 21 untreated retired breeder females exhibited attenuated LH surges on proestrus and subsequently ceased to display regular estrous cycles within 2 months, whereas the other 13 rats showed normal LH and FSH surges and continued to maintain regular cycles. In contrast to these, aged female rats from the previously mated (15-month-old) and the P-implanted (19-month-old) groups exhibited normal profiles of proestrous LH and FSH surges during regular estrous cycles.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1985

Treatment of hot flashes with transdermal estradiol administration.

A randomized prospective double blind study was performed to assess the ability of a transdermal therapeutic system (TTS) delivering estradiol (E2) to suppress hot flashes (HFs) in symptomatic postmenopausal women. Patients were given placebo or E2 in four doses for a 20-day period, and serum gonadotropin and estrogen levels and the occurrences of HFs were measured. Administration of placebo had no measurable effect on either estrogen or gonadotropin levels or the occurrence of HFs. A dose-response relationship was found between the rate of E2 administered and the circulating level of E2, with 25, 50, 100, and 200 micrograms/24 h dosages raising the mean E2 concentrations from mean baseline levels of 5-8 pg/ml to 18, 38, 73, and 100 pg/ml, respectively. Estrone levels also increased with TTS application, but to a lesser extent than did E2 levels. Dose-response reductions of FSH and LH with increasing amounts of E2 administration occurred, but gonadotropin levels were not lowered in any of the patients into the ranges found in premenopausal women. TTS application significantly suppressed the occurrence of HFs at the 50 micrograms/24 h dosage and higher. A significant negative correlation (r = 0.6045; P less than 0.001) between E2 levels and the rates of occurrence of HFs was found during hormone administration. Based on this regression, 50% and 100% reductions of HFs should occur at 61 and 122 pg/ml E2. These data indicate that the transdermal delivery of E2 with these systems significantly reduced the occurrence of HFs and allowed definition of the therapeutic range of hormone replacement in terms of lost ovarian function, as reflected by circulating E2 levels.

Administration, Topical↗