Estrogens and the hypothalamo-pituitary-adrenal axis in man: evidence for normal feedback regulation by corticosteroids.

Estrogen treatment and pregnancy are associated with higher than normal plasma free (nonprotein-bound) cortisol levels. In spite of this, clinical manifestations of steroid excess are not seen in these conditions. To explain this seeming discrepancy, it has been postulated that estrogens may induce tissue resistance to the actions of cortisol, and that one aspect of this resistance may be a higher set-point for ACTH suppression by corticosteroids. This possibility was studied in seven normal women. Plasma total and free cortisol levels as well as urinary cortisol excretion were measured during a control period and during treatment with ethinyl estradiol (100 micrograms/day). During both periods, graded doses of dexamethasone (0.2-mg increments; 0-1.4 mg/day) were administered. Estrogen treatment resulted in elevated plasma total and free cortisol levels, but urinary cortisol excretion was not affected. Dexamethasone administration resulted in a dose-dependent reduction of plasma total and free cortisol as well as urinary cortisol. The dose-response curve for suppression by dexamethasone of urinary cortisol during estrogen treatment was indistinguishable from that during the control period. The dose-response curve for plasma free cortisol suppression suggested that during estrogen treatment, slightly more dexamethasone was required to suppress free cortisol. However, this effect was small. In view of the overall data, we conclude that 1) estrogen does not increase integrated free cortisol prevailing in vivo; 2) estrogen does not significantly alter the hypothalamic or pituitary set-point for ACTH suppression by corticosteroid; 3) the elevation of plasma free cortisol is relatively minor and possibly an in vitro phenomenon; and 4) the present findings are compatible with the absence of clinical hypercorticism in hyperestrogenized states.

Biphasic change in pituitary capacity induced by estrogen in hypogonadal women.

PIP: 5 healthy postmenopausal women aged 52-59 years with elevated gonadotropin levels and low estradiol (E2) (10+ or -1.5 pg/mol) concentrations volunteered for this study which measured changes in responses to pulses of luteinizing hormone-releasing factor (LHF) (10 mcg at 2-hour intervals 3 times) and thyroid-releasing factor (TRF) (200 mcg at 2-hour intervals 3 times) for luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin (PL) before and during administration of a large dose of ethinyl estradiol (EE) (400 mcg/day) for 5 days. Responses to LRF and TRF stimulation on the 2nd and 5th days of EE treatment were studied in 2 experimental periods in the same individual at an interval of at least 10 weeks between treatments. During 5 days of EE treatment, LH 1st declined (50%) and then returned to the original level, forming a previously observed U-shaped curve. The initial fall in basal FSH level was not followed by a return to pretreatment level. These changes were accompanied by an exponential increase of more than 3-fold in the PL levels. The bidirectional pattern of LH release was associated with parallel changes in pituitary sensitivity to a 10-mcg pulse of LRF. Pituitary reserve, defined as the response to the 2nd and 3rd pulses of LRF, exhibited unidirectional augmentation. This progression in PL release upwards was unaccompanied by changes in pituitary PL sensitivity and reserve. The contribution of hypothalamic LRF and dopamine in the participation of these functional changes of LH, FSH, and PL are discussed.^ieng

Antiepileptic medication and oral contraceptive interactions: a national survey of neurologists and obstetricians.

Hepatic enzyme-inducing antiepileptic drugs (AEDs) lower oral contraceptive (OC) sex hormone levels approximately 40% and increase the risk of unplanned pregnancies in women with epilepsy. AEDs also increase the risk of birth defects in offspring of women with epilepsy. We performed a national survey to determine obstetricians' and neurologists' knowledge of OC and AED interactions and the risk of birth defects for women with epilepsy taking AEDs. We received responses to a mailed questionnaire from 160 of 1,000 neurologists (16%) and 147 of 1,000 obstetricians (15%) from 47 states. Practice demographics and ages of responders were typical for U.S. neurologists and obstetricians. Ninety-one percent of neurologists and 75% of obstetricians said they treat women with epilepsy of child-bearing age. Only 4% of the neurologists and none of the obstetricians, however, knew the effects of the six most common AEDs on OCs, even though 27% of neurologists and 21% of obstetricians reported OC failures in their patients taking AEDs. Although increasing OC doses can compensate for insufficient OC sex hormone levels due to AEDs, most physicians do not increase the doses. Even though the risk of birth defects for the offspring of women with epilepsy is 4 to 6%, up from the background level of 2%, 44% of neurologists thought the risk was lower (0 to 3%), and some of the respondents guessed that it was as high as 50%. Many neurologists and obstetricians do not have accurate information to counsel women with epilepsy properly about their contraceptive and pregnancy choices.

PIP: Responses from 160 of 1000 neurologists (16%) and 147 of 1000 obstetricians (15%), selected from an American Medical Association listing to receive a mailed questionnaire, revealed a disturbing lack of knowledge about the interactions between antiepileptic medications and oral contraceptives (OCs). Hepatic enzyme-inducing antiepileptic drugs lower OC estradiol levels by about 40% and may reduce free progestin levels, thereby increasing the risk of unplanned pregnancy; moreover, antiepileptics increase the risk of birth defects in their epileptic users, who already have a 4-6% increased risk of such defects. Physicians can reduce, but not prevent, the risk of unwanted pregnancy by increasing the OC estradiol dose to at least 50 mcg and prescribing valproic acid and gabapentin (non-enzyme-inducing antiepileptics). 91% of neurologists and 75% of obstetricians reported that they treated epileptic women of childbearing age, and 27% of the former and 21% of the latter physicians acknowledged cases of OC failure in these patients. Only 4% of the neurologists and none of the obstetricians knew the effects of the 6 most common antiepileptic drugs on OCs. Just 41% of neurologists and 43% of obstetricians routinely had patients adjust their OC doses if they were taking antiepileptics. Such adjustment was more likely among physicians who had an epileptic patient with an unintended pregnancy and those who had accurate knowledge of OC-antiepileptic drug interactions. 44% of neurologists and 23% of obstetricians underestimated the birth defects risk as 0-3%. Since the physicians who chose to respond to this survey were presumably more concerned and knowledgeable about the reproductive effects of antiepileptic drugs than those who chose not to respond, continuing education efforts are urged to enable health care providers to counsel epileptic women about contraception.

Changes in haemostatic variables induced by oral contraceptives containing 50 micrograms or 30 micrograms oestrogen: absence of dose-dependent effect on PAI-1 activity.

Several studies have suggested a dose-response relation between the oestrogen content of oral contraceptive (OC) and the risk of both venous thrombosis and arterial disease, when oestrogen doses were higher than 50 micrograms. However, there is no clear epidemiological evidence for a decrease in thrombotic risk with formulations containing less than 50 micrograms oestrogen. Therefore, we investigated haemostatic variables in users of OC containing either 30 micrograms (35 women) or 50 micrograms (29 women) ethinyl estradiol as compared with non users (64 women) matched for age and smoking status. Mean values of antithrombin activity were significantly lower in 30 micrograms or 50 micrograms oestrogen users than in non users (96% and 98% vs 105%, respectively, p < 0.001), but they were not significantly different between the two groups of OC users. There was a significant increase in mean values of factor VII antigen in women taking either 30 micrograms or 50 micrograms oestrogen as compared with non users (96% and 101% vs 85%, respectively, p < 0.005). Although the difference between both groups of OC users was not significant, a positive linear trend in factor VII levels was observed within the 0-50 micrograms oestrogen range (p < 0.001). Mean levels of fibrinogen were slightly higher in 30 micrograms or 50 micrograms oestrogen users than in non users (2.71, 2.66 g/l vs 2.55 g/l, respectively), but there was no significant difference between the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: In Paris, France, clinicians compared data on 64 women aged 19-40 who used combined oral contraceptives (OCs) for 6-200 months with data on 64 healthy women who did not use OCs for the last two months and who were matched for age and smoking status to investigate activity of plasminogen activator inhibitor 1 (PAI-1), factor VII antigen, fibrinogen concentration, and antithrombin activity in users of OCs containing either 30 mcg or 50 mcg estrogen and in nonusers. OC users exhibited lower mean values of PAI-1 activity than nonusers (4.63-4.89 vs. 6.47 AU/ml; p 0.02). There was no dose-dependent effect of estrogen on PAI-1 activity, however. Antithrombin activity values were much lower in OC users than nonusers (96-98% vs. 105%; p 0.001). The difference between the two groups of OC users was not significant, however. The mean values of factor VII antigen in women using either 30 mcg or 50 mcg estrogen were higher than those for nonusers (96% and 101% vs. 85%, respectively; p 0.005). The difference in factor VII antigen values between the two OC groups was not significant, yet there was a positive linear trend in factor VII levels within the 0-50 mcg estrogen range (p 0.001). No significant difference in the mean fibrinogen levels between the three groups (30 mcg estrogen OC group, 50 mcg estrogen OC group, and nonusers) was observed. Hemostatic variables were not significantly different between 30 mcg estrogen OCs containing 100 mcg, 150 mcg, or 200 mcg levonorgestrel. The researchers could not conduct a valid assessment of the progestogen effect in 50 mcg estrogen OCs due to the wide range of different types of progestogens. These findings suggest an alteration of blood coagulation and fibrinolysis in OC users within the 30-50 mcg estrogen range. Estrogen appears to have a dose-dependent effect on factor VII but no significant effect on PAI-1 activity and other markers of thrombogenic risk and arterial disease risk.

Effect of oestrogen dose on whole blood platelet activation in women taking new low dose oral contraceptives.

Oral contraceptive use is known to cause changes in the haemostatic system. These changes are thought to be related to oestrogen dose and to provide a possible link between the increased risk of thromboembolic disease known to occur in women taking oestrogen containing oral contraceptives. This study measured whole blood platelet activation, serially, in women taking oral contraceptives containing 20 micrograms and 30 micrograms ethinyloestradiol combined with desogestrel. Increased levels of ADP and arachidonic acid induced aggregation were observed in women taking the 30 micrograms ethinyloestradiol combination. Platelet release of beta-thromboglobulin (beta TG) was also significantly increased. Increased collagen induced aggregation was observed but this failed to reach statistical significance for the individual treatment groups. In women taking the 20 micrograms ethinyloestradiol combination, a significant increase was only observed when platelets were stimulated with arachidonic acid. Platelet factor 4 (PF4) levels were unchanged in both groups. Significantly higher levels of beta TG were observed in women taking the 30 micrograms ethinyloestradiol combination compared with women taking the 20 micrograms ethinyloestradiol combination. These results show that oral contraceptive use is associated with platelet activation. Women taking the 20 micrograms ethinyloestradiol combination show less changes in platelet activation than women taking the 30 micrograms ethinyloestradiol combination. This lower dose pill may therefore be particularly suitable for high risk women wishing to use oral contraception.

PIP: To evaluate the effects of low-dose oral contraceptives (OCs) on platelet function, hematologic measures were compared in 45 Irish women taking OCs containing 20 or 30 mcg of ethinyl estradiol as well as 150 mcg of desogestrel. Serum samples were collected before treatment and at 6, 14, and 22 weeks after OC use commenced. ADP induced whole blood platelet aggregation was significantly increased in users of OCs containing 30 mcg of ethinyl estradiol, reaching a maximum at 22 weeks, but not in users of the low-dose OC. A significant increase in collagen induced aggregation was observed when both groups of OC users were combined, but not when either was tabulated separately. Both groups showed significant increases in arachidonic acid induced aggregation. Platelet count, hematocrit, and platelet factor 4 levels were unaffected. Increased levels of beta-thromboglobulin were observed at 6, 14, and 22 weeks in the 30 mcg group; there was no significant change in the 20 mcg group. Since the low-dose 20 mcg ethinyl estradiol OC produced fewer changes in platelet activation, its use is recommended for women with risk factors for thromboembolic disease.

The actions of ethinyloestradiol on the pituitary-adrenal system of the rat.

PIP: A study assessing the effects of estrogen on the pituitary-adrenal axis in rats is reported. In a series of experiments, rats were subjected to single and multiple doses of ethinyl estradiol (EE) and injections of ACTH. Administration of single doses of EE to quiescent rats brought increased plasma and adrenal gland corticosterone concentrations and in vitro corticosteroid production. In animals stressed by ether vapor, the plasma and in vitro corticosterone values were 40% lower than in controls although adrenal corticosterone levels were higher. Treatment with 500 mcg/kg EE per day for 7 days resulted in loss of body weight and hypertrophied, hyperdemic adrenal and pituitary glands in rats sacrificed 1 day after treatment. Rats studied 9 days after treatment showed normal growth and a regression in adrenal size but not in pituitary size. Plasma corticosterone concentration was unchanged 1 day after the 7-day treatment, adrenal weight increased by 58%, and in vivo steroid production was reduced suggesting a distinct hypersecretion of ACTH. Plasma protein binding capacity for corticosterone was unchanged by the 7-day treatment. After 9 days of rest from the EE regimen, an ACTH injection restored in vitro corticosteroid production to normal levels and raised plasma and adrenal content levels in stressed rats which suggests that the adrenal gland regained its function more quickly than the pituitary. Injection with long-acting ACTH caused a 56% increase in adrenal weight and no change in pituitary weight. Adrenal activity was not changed by ACTH treatment suggesting that the adrenal gland was insensitive to an acute release of endogenous ACTH. Inhibition of the pituitary-adrenal response to stress is most likely caused by inhibition of cholesterol synthesis although lack of precursor corticoid secretion due to exhaustion must be considered as a cause. Inhibition of the stress response after extended ACTH treatment is suggested to be due to a decreased sensitivity of the adrenal cortex although a reduction of circulating cholesterol cannot be excluded as a cause.^ieng

Developmental correlation of higher levels of estrogen binding by macromolecules in rat liver supernatant and of increases in plasma renin substrate levels after estrogen administration.

PIP: Developmental correlation of higher levels of estrogen binding by macromolecules in rat liver supernatant and of increases in plasma renin substrate levels after estrogen administration is reported. Gel filtration columns were used to separate bound from free radioactivity in studying binding of radioactive estradiol to tissue supernatants. The liver of the prepubescent female rat has less estrogen-specific binding macromolecules than the adult (p less than .01). This difference in quantity was maintained when binding activities were partially purified by precipitation with ammonium sulfate at 30% saturation. After administration in vivo of 100 mcg of ethinyl estradiol (sc), plasma renin substrate (PRS) levels increased 167% above control in the adult female rat (p less than .05). The corresponding increase was only 15% in the prepubescent rat. In contrast, renin substrate levels were significantly increased in both the prepubescent and adult by administration of 4 mg/kg of dexamethasone (p less than .05). The marked increase in the amount of estrogen binding and PRS responsiveness to estrogen administration with sexual maturation indicates that the estrogen-binding protein may be an estrogen receptor involved in modulating synthesis of at least 1 plasma protein.^ieng

Influence of chlorpromazine on the positive and negative feed-back mechanism of oestrogens in man.

PIP: It was determined whether all the different neuroendocrine actions of estrogen are competitively antagonized by phenothiazines to test the putative analogy between the 2 types of molecular receptor. 12 men aged 22-25 years were tested on 3 days and then given 2 X 20 mg ethinylestradiol (EE) for 4 days with either 2 X 50 mg chlorpromazine (6 cases) or a placebo (6 cases). Neurohypophyseal activity and adenohypophyseal activity were tested. There was a lack of significant changes in pulse, blood pressure, body weight, and psychosexual factors. Blood alkaline phosphatases decreased in all 12 men after estrogen, and an inhibitory effect of estrogens alone was seen on blood FSH and on the 2 and 5 fraction of urinary 17-keto-steroids. The neurophysine basal level and the growth hormone peak response to hypoglycemia showed a stimulatory effect. There was no effect on FSH by chlorpromazine or on the inhibition of 17-keto-steroids due to estrogens. However, chlorpromazine lessened the neurophysine increase and abolished the facilitatory effect of estrogens on growth hormone responsibeness to hypoglycemia. In 60% of the cases TSH blood levels were undetectable and unvaried.^ieng

Differential lipemic and proteinemic response to oral ethinyl estradiol and parenteral estradiol cypionate.

Oral synthetic estrogen administration to normal women has been shown to result in both a lipemic and a proteinemic response. To determine whether parenteral estrogen administration would have similar results, the effects of intramuscular depo-estradiol cypionate on serum lipids and ceruloplasmin were examined. The oral and parenteral estrogens chosen for this study are frequently used therapeutically and varying doses in the range of those commonly employed clinically were given to the experimental subjects. Following oral ethinyl estradiol (20, 50, and 100 micrograms every 12 hr) comparable and significant increases in triglyceride (73 +/- 6 to 128 +/- 10 mg/dl, p < .001), ceruloplasmin (87 +/- 4 to 188 +/- 11 mg/dl, p < .001), and HDL-cholesterol (60 +/- 2 to 74 +/- 3 mg/dl, p < .001) were observed. In contrast, despite substantial increases in serum estrogens, parenteral estrogen administration (depo-estradiol cypionate, 5 and 10 mg) failed to result in alterations in any of the measured parameters. Thus, the route and/or type of estrogen administered may determine the proteinemic and lipemic effects of estrogen in man.

PIP: This study looked at the effect of a commonly used estrogen preparation, parenteral depo-estradiol cypionate, on several metabolic parameters and compared the results of known alterations which follow oral ethinyl estradiol. The metabolic parameters studied were serum cholesterol, triglyceride (TG), ceruloplasmin, and high-density lipoprotein (HDL) cholesterol. Doses of agents used are common therapeutic ones. After oral ethinyl estradiol (20, 50, and 100 mcg every 12 hours) significant increases in TG (73+ or -6 to 128+ or -10 mg/dl, P .001), ceruloplasmin (87+ or -4 to 188+ or -11 mg/dl, P .001), and HDL-cholesterol (60+ or -2 to 74+ or -3 mg/dl, P .001) were observed. In contrast, despite substantial increases in serum estrogens, parenteral estrogen administration (depo-estradiol cypionate, 5 and 10 mg) failed to result in alterations in any of the measured parameters. Thus, the route of contraceptive agent administration may affect the proteinemic and lipemic responses in humans.

Norgestrel and ethynyl estradiol: a new low-dosage oral agent for fertility control.

PIP: To study the safety and efficacy of a norgestrel-ethinyl estradol oral contraceptive compound, 300 Mexican women, 16-42 years of age were orally administered .5 mg norgestrel and .05 mg ethinyl estradiol (Ovral) daily over a total of 3175 study cycles. Most of the women were poor., uneducated and of high parity. None of the patients in the study became pregnant, even in the cycles where 1 or more doses were omitted. The menstrual cycle remained basically unaltered with breakthrough bleeding or spotting sometimes reported, usually when doses were missed. Unexplained amenorrhea occurred in 1.2% of the cycles. Though 5% of the women were ovulatory at one time of another as determined by pregnandiol levels, no pregnancy resulted, which is probably explained by changes in the cervical mucus caused by the pills making an inhospitable environment for sperm migration. Psychosomatic-related side-effects included nausea, headache and decreased libido in less than 1% of the cycles. Chloasma aggravated by poor dietary intake occurred in .5% of the cycles. No malignant, peripheral vascular or other serious disease occurred during the treatment and no significant endometrial alterations were seen.^ieng

Serum steroid binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel.

The oral administration of 150 micrograms desogestrel and 30 micrograms ethinyl estradiol (EE2) increases (P less than 0.001) serum concentrations of sex-hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG), whereas treatment with 150 micrograms levonorgestrel and 30 micrograms EE2 only increases serum CBG concentrations. No changes in serum albumin concentrations occurred during or after treatment with either preparation, and increases in SHBG and CBG returned to the pretreatment values 1 month after treatment ceased. The serum distribution of levonorgestrel was unchanged during treatment, whereas the increase in serum SHBG concentrations after treatment with the preparation containing desogestrel decreased (P less than 0.001) the percentage of non-protein-bound 3-keto- desogestrel and the percentage of albumin-bound 3-keto- desogestrel but increased (P less than 0.001) the SHBG-bound fraction. Oral contraceptives containing either progestogen decrease the mean serum non-protein-bound testosterone concentrations, especially during treatment with desogestrel (P less than 0.001), and desogestrel may therefore by the more appropriate progestogen for the treatment of women prone to androgenic side effects.

PIP: The oral administration of 150 mcg desogestrel and 30 mcg ethinly estradiol (EE2) increases (P0.001) serum concentrations of sex hormone binding globulind (SHBG) and corticosteroid-binding globulin (CBG) whereas treatment with 150 mcg levonorgestrel and 30 mcg EE2 only increases serum CBG concentrations. No changes in serum albumin concentrations occurred during or after treatment with either preparation, and increases in SHBG and CBG returned to the pretreatment values 1 month after treatment ceased. The serum distribution of levonorgestrel was unchanged during treatment, whereas the increase in serum SHBG concentrations after treatment with the preparation containing desogestrel decreased (P0.001) the percentage of nonprotein-bound 3-keto-desogestrel and the precentage of albumin-bound 3-ketodesogestrel but increased (P0.001) the SHBG-bound fraction. Oral contraceptives containing either progestogen decrease the mean serum nonprotein-bound testosterone concentratious, especially during treatment with desogesgtrel (P0.001), and desogestrel may therefore be the more appropriate progestogen for the treatment of women who are prone to androgenic side effects.

Sperm storage in the human cervix: a quantitative study.

Twenty-five women scheduled for hysterectomy for nonmalignant disease participated in the study. Sperm storage in endocervical crypts was examined in three groups of patients: nine women pretreated with estrogen and inseminated with normal semen, nine women pretreated with gestagen and inseminated with normal semen, and seven women pretreated with estrogen and inseminated with abnormal semen. The number of crypts containing spermatozoa (colonized crypts) and the sperm density per crypt were examined in serially sectioned cervices. In estrogen-pretreated cervices both the percentage of colonized crypts and the sperm density were significantly higher than in gestagen-pretreated cervices. Large and giant crypts proved to be the main storage facility for spermatozoa. The localization of crypts along the endocervical canal did not influence sperm storage. The quality of semen appeared to be of critical importance to sperm storage. The percentage of colonized crypts and sperm density were severly reduced in patients inseminated with abnormal semen.

PIP: This study investigated whether estrogen and gestagen influence the capacity pattern and retention time of sperms in endocervical crypts, determined whether the mean number of sperms in the lower part of the cervix was similar to or different from that in the upper part, and established whether the retention time of sperms in cervical crypts differed in the case of abnormal semen as compared with normal semen. 25 women, scheduled for hysterectomy for nonmalignant indications were studied. 3 groups of patients were studied for sperm storage measurements: 9 women were pretreated with estrogen and inseminated with normal semen; 9 women were pretreated with gestagen and inseminated with normal semen; and 7 women were pretreated with estrogen and inseminated with abnormal semen. Serially sectioned cervixes were studied to quantitate the number of crypts containing sperm (colonized crypts). In estrogen-pretreated subjects, the percents colonized crypts and sperm density were significantly higher than in gestagen-pretreated subjects' cervixes. The main storage of sperm occurred in large and giant crypts. Localization of crypts along the endocervical canal had no influence on sperm storage. Semen quality was of critical importance in sperm storage; the percentages of colonized crypts and sperm density were severely reduced in subjects inseminated with abnormal semen.

Comparison of the effects of contraceptive steroid formulations containing two doses of estrogen on pituitary function.

A pituitary stimulation test with gonadotropin-releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH) was undertaken to determine (1) whether pituitary responses to GnRH vary in individual women taking oral contraceptive steroids over time, (2) whether a less suppressive pituitary gonadotropin effect is produced by formulations containing less than 50 microgram of estrogen, and (3) to obtain more information concerning prolactin secretion in users of oral contraceptive steroids. The same subjects who had had a suppressed luteinizing hormone (LH) and follicle-stimulating hormone (FSH) response 6 to 9 months previously also had a suppressed response, indicating that this effect persists over time. Contraceptive formulations containing less than 50 microgram of estrogen have a lesser suppressive effect on LH release than do formulations containing 50 microgram of estrogen or more. The basal prolactin (PRL) response as well as the maximal PRL response to TRH were found to be significantly greater in subjects using oral contraceptives than in the control subjects. However, no difference in PRL response was found between the subjects using low or high doses of estrogen fomulations.

PIP: A comparison of the effects of contraceptive steroid formulations containing 2 doses of estrogen on pituitary function is reported. The gonadotropin-releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH) stimulation tests were carried out with 11 control women, 23-38 years of age, and 39 women receiving various oral contraceptive (OC) formulations. The responses to GnRH stimulation were similar in the same subjects who had been stimulated 6-9 months previously, indicating that the effect persists over time. OCs containing less than 50 mcg of estrogen showed a lesser suppressive effect on luteinizing hormone (LH) release than did OCs containing 50 mcg or more of estrogen (p .001). Peak serum follicle stimulating responses were significantly lower (p .01) than those of controls, but there was no marked difference between the 2 groups of OC users. Basal prolactin (PRL) response as well as the maximal PRL response to TRH were significantly greater (p .025 and p .05), respectively) in subjects using OCs than in the control subjects. It is concluded that OCs have a suppressive effect on pituitary gonadotropin release in most users, which is independent of the dose of estrogen.

Comparative studies of the ethynyl estrogens used in oral contraceptives. VI. Effects with and without progestational agents on carbohydrate metabolism in humans, baboons, and beagles.

Human subjects, baboons, and beagles were given cyclic regimens of ethynylestradiol or mestranol; after a number of such cycles, concurrent administration of norethindrone acetate, dl-norgestrel, or megestrol acetate was introduced for a similar number of cycles. Carbohydrate tolerance was evaluated by oral glucose tolerance testing in the human subjects and by intravenous glucose tolerance testing in the baboons and beagles. In the human subjects, neither mestranol nor ethynylestradiol at daily doses of 50 to 100 microgram/day produced any effect on fasting glucose levels or on glucose tolerance even after six cycles of treatment. The addition of the progestational compounds also had no effect on these two variables. In baboons, ethynylestradiol and mestranol were bioequivalent and produced a dose-related decrease in the glucose disposal rate. All three progestational agents counteracted this effect in a comparable manner. In beagles, on the other hand, estrogens produced an increase in the glucose disposal rate, and the addition of progestational agents produced an initial fall and a subsequent return to pretreatment levels.

PIP: In a comparison of the glucose metabolic effects of certain estrogens and progestins, 163 normal females received either 50 or 80 mcg/day ethinyl estradiol or 50, 80, or 100 mcg/day mestranol for 21 days over 6 cycles. At the end of 6 cycles each group received additionally either 2.5 mg/day norethindrone acetate, 2 mg/day megestrol acetate, or .5 mg/day dl-norgestrel. Simulations of this regimen were carried out in beagles and baboons using lower dosages and treatment durations of 4 instead of 6 cycles. Glucose tolerance tests were administered orally to the humans and iv to the animals in the latter part of certain treatment cycles. In humans, no significant effects were found for type or dose of estrogen, cycle number, addition of progestin, or any of their interactions. In the animals, estrogen lowered fasting plasma glucose both in the baboons (p .05) and in the beagles (p .001), a trend which reversed spontaneously until control values prevailed at the end of the 4th estrogen-treatment cycle. Progestins had no effect. Glucose assimilation rates (K values) were significantly depressed over the first 4 cycles in baboons (p .001) but rose with the addition of progestins. In beagles, by contrast, the K values rose (p .001) and fell again with the introduction of progestin treatment. It is concluded that baboons and beagles are poor models for examination of human carbohydrate metabolism.

Mode of action of dl-norgestrel and ethinylestradiol combination in postcoital contraception. III. Effect of preovulatory administration following the luteinizing hormone surge on ovarian steroidogenesis.

A combination of 1.0 mg dl-norgestrel and 0.1 mg ethinylestradiol was administered orally at 18 hours after the detection of luteinizing hormone rise and again at 30 hours in five healthy volunteers with normal menstrual cycles. The effects on ovarian function were studied by comparing the daily serum levels of progesterone (P), 17 alpha-hydroxyprogesterone, and estradiol (E2) measured in a control (placebo) cycle with those in two consecutive treatment cycles. Treatment did not alter the steroid levels in one subject. P was suppressed in one or both treatment cycles of four subjects. E2 was suppressed in both treatment cycles of one subject and produced widely fluctuating patterns in another. The hormonal patterns in the two consecutive treatment cycles of the same individual were similar in all but one instance, where only the P level in the second treatment cycle was diminished. These results showed that this treatment can elicit steroidogenic responses of varying degrees and duration. The contraceptive action may lie in the altered P and/or E2 level at certain points in the menstrual cycle.

PIP: A combination of 1.0 mg dl-norgestrel and 0.1 mg ethinyl estradiol was administered orally at 18 hours after detection of luteinizing hormone and again at 30 hours in 5 healthy volunteers with normal menstrual cycles. The effects on ovarian function were studied by comparing the daily serum levels of progesterone (P), 17alpha-hydroxyprogesterone, and estradiol (E2) measured in a control (placebo) cycle with those in 2 consecutive treatment cycles. Treatment did not alter the steroid levels in 1 subject. P was suppressed in 1 or both treatment cycles of 4 subjects. E2 was suppressed in both treatment cycles of 1 subject and produced widely fluctuating patterns in another. The hormonal patterns in the 2 consecutive treatment cycles of the same individual were similar in all but 1 instance, where only the P level in the 2nd treatment cycle was diminished. These results showed that this treatment can elicit steroidogenic responses of varying degrees and duration. The contraceptive action may lie in the altered P and/or E2 level at certain points in the menstrual cycle.

Comparative studies of the ethynyl estrogens used in oral contraceptives. VII. Effects with and without progestational agents on ultracentrifugally fractionated plasma lipoproteins in humans, baboons, and beagles.

Ethynyestradiol and mestranol, in doses ranging from 50 to 100 microgram/day, were given to women in 21-day cycles; baboons and beagle dogs received 1 and 4 microgram/kg/day in a similar regimen. After a number of such cycles, megestrol acetate, norethindrone acetate, or dl-norgestrel was given concomitantly. Protein, cholesterol, triglyceride, and phospholipid levels were determined in total plasma and in ultracentrifugally separated lipoprotein fractions. Over the dosage range studied, the effects of the two kinds of estrogen were indistinguishable. Except for human total plasma triglyceride, no dose-related differences were observed. The lowering of serum protein and the increase in cholesterol induced by estrogen were more pronounced in baboons and beagles than in human subjects. The cholesterol-depressing effect of progestational compounds observed in humans was very pronounced in baboons but absent in beagles. In all three species, estrogen increased the lipoprotein fraction cholesterol, except for human low-density lipoprotein cholesterol, which was decreased. Human plasma triglyceride and phospholipid increased on estrogen administration and were decreased by the progestins; in the two animal species, triglyceride is normally very low and the estrogen-induced changes were negligible; the phospholipid rose with estrogen but was unaffected by progestins. In sum, the two animal species show many similarities to, as well as important differences from, the human response of plasma lipids to various contraceptive steroids.

PIP: In this comparative study, ethinyl estradiol and mestranol (dose range, 50-100 microg/day) were given to women in a 21-day cycle; baboons and beagle dogs received 1 and 4 microg/kilog/day in a similar regimen. After a number of cycles, mestranol acetate, norethindrone acetate, or d,1-norgestrel was given concomitantly. Protein, cholesterol, triglyceride and phospholipid levels were determined in total plasma and in ultracentrifugally separated lipoprotein fractions. Effects of the 2 kinds of estrogens were indistinguishable over the dosage range studied. Except for human total plasma triglyceride (P .001), no dose-related differences were observed. Lowering of serum protein and increase in cholesterol induced by estrogen were more pronounced in the 2 animal species than in humans. The cholesterol-depressing effect of progestational compounds observed in humans was very pronounced in baboons but was absent in beagles. In all 3 species, estrogen increased the lipoprotein fraction cholesterol, except for human low-density lipoprotein cholesterol, which was decreased. Human plasma triglyceride and phospholipid increased on estrogen administration and were decreased by progestins. In beagles and baboons, triglyceride is normally very low and the estrogen-induced changes were negligible; phospholipid rose with estrogen but was unaffected by progestins.

Ovulation inhibition with sequential therapy. A continuing clinical study of fertility control.

PIP: A study on sequential ovulation inhibiting pill, 5048-1Z(Oracon), with the following preparation --16 white tablets, each containing .1 mg ethinyl estradiol and 5 colored tablets each with the same does of ethinyl estradiol plus 25 mg dimethisterone--is presented. Another group of patients received a more potent and newer orally effective progestin, megestrol acetate, the tablets being the same except instead of 25 mg dimethisterone in the last 5 tablets there were 5 mg of megestrol acetate. A third group received the megestrol acetate formulation but the dose was reduced to 2.5 mg and then to 2 mg megestrol acetate. The sequential regimen more closely resembles the physiologic hormonal pattern. The Oracon preparation with 25 mg dimethisterone was effective in fertility control. The formulation with megestrol acetate in both dose forms was found to be effective for the inhibition of ovulation and control of conception. Breakthrough bleeding and missed menstrual periods were uncommon with the sequential regimen.^ieng

A comparison of high-dose estrogens versus low-dose ethinylestradiol and norgestrel combination in postcoital interception: a study in 493 women.

Ethinylestradiol (EE), at a dosage of 5 mg/day for 5 consecutive days (5 mg EE), has generally been used for interception. A combination of 200 micrograms EE and 2 mg dl-norgestrel (EE + NG) was proposed as an effective alternative. Efficacy and tolerance of these methods were compared in a randomized, double-blind study. A group of 465 women was studied with a follow-up rate of 94.3%. In the 5 mg EE group a pregnancy rate of 0.9% was observed, and in the EE + NG group a rate of 0.4% was found. These rates differ significantly from the expected rates (P less than 0.0005, in both series). Nausea was noted in 59.1% of the 5 mg EE group and in 54.0% of the EE + NG series. Nausea and vomiting occurred in 20.8% and 15.8%, respectively. The efficacy of both methods as alternative morning-after medication was confirmed. The new method is preferable because treatment is limited to only 1 day.

PIP: Ethinyl estradiol (EE), at a dosage of 5 mg/day for 5 consecutive days (5 mg EE) has generally been used for interception. A combination of 200 mcg EE and 2 mg dl--norgestrel (EE+NG) was porposed as an effective alternative. Efficacy and tolerance of these methods were compared in a randomized, double-blind study. A group of 465 women was studied with a follow-up rate of 94.3%. In the 5 mg EE group, a pregnancy rate of 0.9% was observed, and in the EE+NG group, a rate of 0.4% was found. These rates differ significantly from the expected rates (P0.0005, in both series). Nausea was noted in 59.1% of the 5 mg EE group in and 54.0% of the EE+NG group. Nausea and vomiting occurred in 20.8% and 15.8% respectively. The efficacy of both methods as alternative to morning-after medication was confirmed. The new method is preferable since treatment is limited to only 1 day.

Comparison of ethinylestradiol and mestranol in sequential-type oral contraceptives in their effects on blood glucose and serum insulin in oral glucose tolerance tests.

Forty 3-hour oral glucose tolerance tests (OGTTs) were performed in 10 assumedly healthy female volunteers 19 to 30 years old, each serving four times as her own control. Each subject was taking a sequential type oral contraceptive containing either 50 microgram of ethinylestradiol or 80 microgram of mestranol alternatingly in four consecutive treatment cycles. The OGTTs were performed on the 6th day of each cycle, during pure estrogen medication. Blood glucose and serum insulin values did not differ significantly under either estrogen as tested by the t-test for paired observations. Our results do not support the findings of others that mestranol has a more pronounced or even exclusively adverse effect on glucose tolerance as compared with ethinylestradiol.

PIP: 10 female volunteers (19-30 years) received ethinyl estradiol (EE) and mestranol (ME) in order to determine whether treatment would influence carbohydrate metabolism. EE dose was 50 mcg and ME dose was 80 mcg. In each treatment cycle the estrogenic compound was given for 7 days, followed by 15 days of combined treatment with a gestagenic compound and a treatment-free interval of 6 days during which withdrawal bleeding occurred. On the 6th day of each treatment cycle on oral glucose tolerance test (OGTT) was performed. Blood smaples were obtained every 30 minutes over 3 hours and assayed for blood glucose and for serum insulin. The differences in blood glucose levels or serum insulin between EE cycles and ME cycles were insignificant.

Carbohydrate metabolism of Indian women taking steroid contraceptives.

Three parameters, serum glucose, insulin, and growth hormone levels, were used to measure carbohydrate metabolism in 25 women not using steroid contraceptives, 48 women using combination oral contraceptives, and 27 women using low-dose progestogen oral contraceptives. Women in the combination contraceptives group had significant modifications in the responses of all three parameters studied. A bias toward modification was also seen in the normal tests of the combination group. The low-dose progestogen, megestrol acetate, did not cause similar changes in glucose, insulin, and growth hormone values.

PIP: A study was undertaken to report the responses of serum glucose, insulin, and growth hormone levels to iv glucose injections in 48 women using a combination oral contraceptive (OC) (OVral), in 27 women on dialy progestogen alone (megestrol acetate), and in 25 non-OC users. Women taking combination OCs had significant modifications in the responses of all 3 parameters ( p less than .05). The normal tests of the combination OC group also exhibited a tendency toward modification. Changes in serum glucose, insulin, and growth hormone values were absent in the low-dose progestogen group. These studies indicate that the mechanisms whereby OCs modify carbohydrate metabolism are unknown. More research is necessary to provide information concerning metabolic effects of hormonal contraceptives.