Comprehensive Sex Steroid Profiling in Multiple Tissues Reveals Novel Insights in Sex Steroid Distribution in Male Mice.

A comprehensive atlas of sex steroid distribution in multiple tissues is currently lacking, and how circulating and tissue sex steroid levels correlate remains unknown. Here, we adapted and validated a gas chromatography tandem mass spectrometry method for simultaneous measurement of testosterone (T), dihydrotestosterone (DHT), androstenedione, progesterone (Prog), estradiol, and estrone in mouse tissues. We then mapped the sex steroid pattern in 10 different endocrine, reproductive, and major body compartment tissues and serum of gonadal intact and orchiectomized (ORX) male mice. In gonadal intact males, high levels of DHT were observed in reproductive tissues, but also in white adipose tissue (WAT). A major part of the total body reservoir of androgens (T and DHT) and Prog was found in WAT. Serum levels of androgens and Prog were strongly correlated with corresponding levels in the brain while only modestly correlated with corresponding levels in WAT. After orchiectomy, the levels of the active androgens T and DHT decreased markedly while Prog levels in male reproductive tissues increased slightly. In ORX mice, Prog was by far the most abundant sex steroid, and, again, WAT constituted the major reservoir of Prog in the body. In conclusion, we present a comprehensive atlas of tissue and serum concentrations of sex hormones in male mice, revealing novel insights in sex steroid distribution. Brain sex steroid levels are well reflected by serum levels and WAT constitutes a large reservoir of sex steroids in male mice. In addition, Prog is the most abundant sex hormone in ORX mice.

Drug Interactions with Gender-Affirming Hormone Therapy: Focus on Antiretrovirals and Direct Acting Antivirals.

INTRODUCTION: Gender-affirming care may include hormonal therapy to attain desired health outcomes in transgender (trans) individuals. To provide safe, affirming medical care for trans patients, health care providers must identify and manage drug-drug interactions (DDIs) between gender affirming hormonal therapy (GAHT) and other medication therapies. AREAS COVERED: This review summarizes available data on DDIs between GAHT and antiretrovirals (ARVs) or hepatitis C direct acting antivirals (DAAs). Potential pharmacokinetic and pharmacodynamic DDIs are predicted based on GAHT, ARV, and DAA pharmacology and adverse event profiles. Clinical management strategies are discussed. EXPERT OPINION: GAHT may be involved in pharmacokinetic and/or pharmacodynamic DDIs. Certain ARV classes (non-nucleoside reverse transcriptase inhibitors, protease inhibitors) may alter GAHT disposition, whereas selected ARVs (unboosted integrase inhibitors, doravirine, or rilpivirine) may have less impact on GAHT. DAAs may interact with GAHT, but the clinical relevance is unclear. ARV- and/or DAA-associated side effects (including depression, cardiovascular disease, hyperlipidemia) are important to consider in the clinical management of trans patients. Clinicians must evaluate potential DDIs and overlapping side effects between ARVs, DAAs and GAHT when providing care for trans patients.

Pilot study: absorption and efficacy of multiple hormones delivered in a single cream applied to the mucous membranes of the labia and vagina.

BACKGROUND/AIMS: There is a lack of evidence in the literature supporting vaginal application of a combination hormone-containing cream for local and systemic symptom relief. This pilot study examined the extent of absorption of a single cream containing estriol, estradiol, progesterone, DHEA, and testosterone. METHODS: A combination cream was administered to 12 postmenopausal women in two differing doses over two independent time periods. Following 28 days (arm 1) and an additional 14 days (arm 2), measurement of hormones in saliva and blood and measurements of symptom relief, patient tolerability, and health-related quality of life (HRQoL) were obtained. RESULTS: The dosage and time of evaluation for study arm 1 was not ideal for providing documented increases in hormone levels. HRQoL measurements supported measured improvement in this arm. The second arm did document absorption of the various hormones when given vaginally. CONCLUSION: This study is the first documenting systemic absorption of multiple hormones by both saliva and blood as well as improvement of HRQoL. This therapy was generally well-tolerated with only 2 patients experiencing minor irritation, not necessitating discontinuation. Additional studies in larger numbers of patients will provide better knowledge for clinicians wanting to provide similar therapy at the lowest effective dose.

Impairment of spermatogonial development and spermiation after testosterone-induced gonadotropin suppression in adult monkeys (Macaca fascicularis).

Human male hormonal contraceptive regimens do not consistently induce azoospermia, and the basis of this variable response is unclear. This study used nine adult macaque monkeys (Macaca fascicularis) given testosterone (T) implants for 20 weeks to study changes in germ cell populations in relation to sperm output. Germ cell numbers were determined using the optical disector stereological method. Four animals achieved consistent azoospermia (azoo group), whereas five animals did not (nonazoo group). T-induced gonadotropin suppression in all animals decreased A pale (Ap) spermatogonia to 45% of baseline within 2 weeks, leading to decreased B spermatogonia (32--38%) and later germ cells (20--30%) after 14 and 20 weeks. Though the reduction in later germ cell types could be primarily attributed to the loss of spermatogonia, the data suggested that some cells were lost during the spermatocyte and spermatid phase of development. B spermatogonial number was more markedly suppressed in azoospermic animals, compared with the nonazoo group, as was the conversion ratio between Ap and B spermatogonia. Abnormal retention of elongated spermatids (failed spermiation) was also prominent in some animals after long-term T administration. We conclude that: 1) the variable suppression of sperm output is attributed to the degree of inhibition of germ cell development from type B spermatogonia onwards, and this is related to the degree of FSH suppression; and 2) inhibition of Ap and B spermatogonial development and of spermiation are the major defects caused by long-term T administration to monkeys.

Effects of female sex hormones and pregnancy on gallbladder prostaglandin synthesis.

To investigate whether female sex hormones and pregnancy induce increased gallbladder synthesis of prostaglandin I2 (PGI2) and prostaglandin E (PGE), we used an in vitro incubation chamber to quantitate the effects of progesterone, estrogen, pregnancy, and pregnancy plus a 2%-cholesterol diet on mucosal and serosal PGI2 and PGE production by the rabbit gallbladder. Neither the female sex hormones nor pregnancy alone caused a significant increase in PGI2 or PGE synthesis. The gallbladders of cholesterol-fed, pregnant rabbits demonstrated significant increases only in serosal synthesis of PGI2. This increased production was equivalent to that noted for gallbladders from nonpregnant rabbits fed a high-cholesterol diet. There were no increases in mucosal synthesis of PGE or of PGI2. Thus, neither elevated levels of progesterone or estrogen nor pregnancy is directly responsible for the increased PGI2 activity in the female gallbladder; conversely, this effect seems to be mediated by the increased biliary concentrations of cholesterol.

The effect of pharmacokinetically guided acute intravenous testosterone administration on electrocardiographic and blood pressure variables.

Previous studies have demonstrated that intravenous testosterone can dilate coronary arteries and increase exercise treadmill time, but the electrocardiographic and hemodynamic effects are unknown. This trial determined the hemodynamic and electrocardiographic effects of dosing intravenous testosterone to achieve a physiologic and a superphysiologic serum testosterone concentration. Twenty men (70.6 +/- 6.2 years) had individualized testosterone bolus and continuous infusions designed to increase the serum testosterone concentration by two (physiologic) and six times baseline (superphysiologic). The men were studied on three occasions when they were randomly allocated to received a placebo, physiologic testosterone regimen, or superphysiologic testosterone regimen. Blood pressures and 12-lead electrocardiograms (ECGs) were taken preinfusion and 28 minutes after initiating the infusion on each visit. The blood pressure (systolic and diastolic) and ECG variables (PR, QRS, QT, QTc, and RR intervals) preinfusion and during the infusion were compared, and the delta changes in the variables were compared between groups. The physiologic testosterone regimen increased the serum testosterone concentration by 2.39 +/- 0.48 times the preinfusion concentration, while the superphysiologic regimen increased it by 6.22 +/- 0.99 times. No significant changes occurred in the blood pressure or ECG variables in any group versus preinfusion values or between the three groups. Exogenously administered intravenous testosterone does not significantly affect the blood pressure or ECG variables when given to achieve physiologic or superphysiologic concentrations.

Ex vivo bioadhesion and in vivo testosterone bioavailability study of different bioadhesive formulations based on starch-g-poly(acrylic acid) copolymers and starch/poly(acrylic acid) mixtures.

Starch-g-poly(acrylic acid) copolymers or grafted starches synthesized by 60Co irradiation or chemical modification and co-freeze-dried starch/poly(acrylic acid) mixtures were evaluated on their ex vivo bioadhesion capacity. The buccal absorption of testosterone from a bioadhesive tablet formulated with the grafted starches or starch/poly(acrylic acid) mixtures was investigated. The results were compared to a reference formulation (physical mixture of 5% Carbopol 974P and 95% Drum Dried Waxy Maize). Rice starch-based irradiated grafted starches showed the best bioadhesion results. Partial neutralization of the acrylic acid with Ca(2+) ions resulted in significantly higher bioadhesion values compared to the reference. Ca(2+) and Mg(2+) partially neutralized maltodextrin-based irradiated grafted starches showed significantly higher bioadhesion values compared to the reference formulation. The chemically modified grafted starches showed significantly higher adhesion force values than for the reference tablet. None of the co-freeze-dried starch/poly(acrylic acid) mixtures showed significantly higher bioadhesion results than the reference (Bonferroni test, P<0.05). A chemically modified grafted starch could sustain the 3 ng/ml plasma testosterone target concentration during +/- 8 h (T(>3 ng/ml)). By lyophilization of a partially neutralized irradiated grafted starch, the in vivo adhesion time (22.0 +/- 7.2 h) and the T(>3 ng/ml) (13.5 +/- 1.3 h) could be increased. The absolute bioavailability of the lyophilized formulation approached the reference formulation. Some of the grafted starches showed to be promising buccal bioadhesive drug carriers for systemic delivery.

Testosterone release from a subcutaneous, biodegradable microcapsule formulation (Viatrel) in hypogonadal men.

Men with hypogonadism require testosterone replacement for optimal health. In the United States, testosterone is currently administered by daily transdermal patches, topical gels or intramuscular injections every 1-3 weeks. Biodegradable polylactide-co-glycolide microcapsules are currently used for long-term drug delivery in humans. Such microcapsules that contain testosterone could provide a better means of long-term testosterone therapy. We therefore studied the pharmacokinetics and pharmacodynamics of testosterone release from testosterone microcapsules in men with hypogonadism. Fourteen men who had been treated previously with testosterone were enrolled in an open-label, prospective study of testosterone microcapsule administration. Subjects were enrolled if 2 consecutive serum total testosterone levels were lower than 8.7 nmol/L after a 4-week washout from testosterone therapy. Subjects were injected with a single dose of either 267 mg (n = 7) or 534 mg (n = 7) of (Viatrel) testosterone microcapsule, and serum total testosterone, dihydrotestosterone, estradiol, sex-hormone binding globulin, luteinizing hormone, and follicle-stimulating hormone levels were determined at days -14, -7, and 0 before the injection; at days 1, 2, and 7 after the injection; and then weekly thereafter for 8-12 weeks. Mean serum total testosterone levels peaked immediately following injection on day 1 at 25.2 +/- 2.6 nmol/L in the 267 mg group and 34.7 +/- 2.4 nmol/L in the 534 mg group. Total serum testosterone levels declined gradually and fell below 8.7 nmol/L at 42 days after injection in the 267 mg group, and 70 days after injection in the 534 mg group. Estradiol and dihydrotestosterone levels followed a similar pattern. Mean serum free testosterone also peaked immediately following injection on day 1 at 0.51 +/- 0.05 nmol/L in the 267 mg group and 0.97 +/- 0.08 nmol/L in the 534 mg group. No significant adverse reactions were seen, although 2 subjects complained of transient tenderness and fullness at their injection sites. We conclude that a single injection of 534 mg of testosterone microcapsules to men with hypogonadism normalizes serum hormone levels for up to 10-11 weeks, albeit with a pronounced early peak and a relatively long period of low-normal serum total testosterone. Subcutaneously administered testosterone microcapsules may provide a safe and convenient method for the long-term treatment of male hypogonadism or testosterone replacement in male contraceptive regimens.

Enhanced skin permeation of sex hormones with novel topical spray vehicles.

The feasibility of using some novel topical spray vehicles for enhanced transdermal delivery of the sex hormones, testosterone (Tes), estradiol (E2), progesterone (Prog), and norethindrone acetate (NA) has been investigated. The new penetration enhancers, padimate O (PadO) and octyl salicylate (OSal) were used and compared with laurocapram (AZ) and oleic acid (OA). A finite dose (5 microL/cm2) of each vehicle was applied to either shed snake skin or swine skin in vitro, and the amount penetrated was measured with flow-through diffusion cells. Partitioning into swine skin was determined after an exposure time of 1 min. Rapid partitioning of Tes and PadO into swine skin occurred after 1 min with 70% and 60% of the applied dose, respectively, remaining in the skin after the unabsorbed dose was removed by rinsing with absolute ethanol. The cumulative amount at 24 h (Q24 h) of Tes penetrating across the snake skin was significantly enhanced (p < 0.05) up to 6-fold for OSal, 3-fold for OA and AZ, and 2-fold for PadO compared to control. Using PadO or AZ, the Q24 h ranged from three- to thirteen-fold over control (p < 0.05) for E2, Prog, and NA. Extrapolation of these data to predict what would happen in humans suggests that it should be possible to deliver clinically relevant amounts of sex hormones in this manner with once daily dosing.

Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy.

The concept of bioavailability is discussed with particular references to the sex steroids. Problems encountered in the measurement of bioavailability of these steroids and the various factors that may affect their bioavailability are briefly described. Information regarding the bioavailability of the estrogens and gestogens, some of which are prodrugs, used in oral contraception and hormone replacement therapy is summarized and the implications regarding the clinical use of these steroids are discussed.

PIP: This review examines the bioavailability of sex steroids used in oral contraceptives and hormone replacement therapy and the implications of the clinical use of these steroids. These steroids include the estrogens (estradiol, estrogen sulfates, ethinyl estradiol) and the gestogens (progesterone, norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate, and medroxyprogesterone acetate). The naturally occurring sex steroids are estradiol, estrogen sulfates, and progesterone or their derivatives. The synthetic sex steroids are ethinyl estradiol, norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate, and medroxyprogesterone acetate. Factors influencing bioavailability of these sex steroids revolve around drug formulation (dosage form, disintegration rate, and dissolution rate), drug characteristics (chemical properties and stability in the gastrointestinal tract), user's characteristics (gastrointestinal and hepatic functions), and possibly smoking, diet, and other drugs. A wide variation exists in the bioavailability values both within any study and between the different studies with the same steroid. Possible reasons for the variability include experimental error, a small number of subjects, the rate and extent of absorption of the compound, the compound's rate of metabolism and elimination (especially hepatic metabolism and elimination), differences in dose, and interaction between the estrogen and the gestogen. Some of the synthetic sex steroids are prodrugs.

Evaluation of Göttingen minipig skin for transdermal in vitro permeation studies.

The optimal skin type for in vitro permeability studies depends on the purpose of the specific transdermal study. In a number of cases, it may be advantageous to use animal skin as an alternative to human skin although they have different characteristics. Recently, Göttingen minipigs have been reported as good models in toxicological and pharmacokinetic studies of drug substances. In this paper, the potential use of skin from the Göttingen minipig is evaluated by studying three model drug substances (nicotine, salicylic acid and testosterone) through skin from humans, domestic pigs and three ages of the Göttingen minipig. An analysis of variance and a Student's t-test showed that both the skin from the Göttingen minipig and the domestic pig possessed transdermal permeabilities, which correlated with human skin and exhibited a lower intra- and intervariation. Furthermore, it was shown that permeability and variation of fluxes through skin from Göttingen minipigs were dependent on the age of the minipig and of the drug substance. It is concluded that the Göttingen minipig, like the domestic pig, is a good skin model for in vitro permeation through human skin.

[Epilepsy and women's life: particularities of their management. Literature review]. / Epilepsie et vie de la Femme : Specificite de la Prise en Charge Revue de la Litterature.

Eight in 1,000 people in the world suffer from epilepsy, and 80 % of them are in the developing countries [1]. Sub-Saharan Africa and Latin America have higher median prevalence's 15.4 % and 12.4 %, respectively, compared to the prevalence in Europe, 5.4 %, and in North America, 5-10 % [2]. On this epidemiological inequality overlays a considerable disparity in the quality of care given to people with epilepsy, between developed and developing countries, and rural and urban areas. In this context, one of the most controversial subject regarding epilepsy is the care given to epileptic patients and their offspring. In fact, being a woman with epilepsy is not as being a man. The specific concerns about women with epilepsy are essentially sexual development, contraception, reproduction, fertility, and anatomic and cognitive teratogenicity of anti-epileptic drugs. The awareness campaign of women with epilepsy starts from puberty until menopause. About one third of epileptic women experience variations in their disease linked to menses, probably due to the neurotoxicity of oestrogens (not counterbalanced by progestatives). The problem with the teratogenicity of anti-epileptic drugs is not resolved yet despite the availability of new molecules. A close collaboration between health practitioners (obstetricians and neurologists) and an awareness of health professionals are essential for a global care of pregnant epileptic women or at age to conceive.

In vitro inhibition of CYP1A2 by model inhibitors, anti-inflammatory analgesics and female sex steroids: predictability of in vivo interactions.

The cytochrome P450 enzyme CYP1A2 is crucial for the metabolism of many drugs, for example, tizanidine. As the effects of several non-steroidal anti-inflammatory drugs (NSAID) and female sex steroids on CYP1A2 activity in vitro are unknown, their effects on phenacetin O-deethylation were studied and compared with the effects of model inhibitors in human liver microsomes, followed by prediction of their interaction potential with tizanidine in vivo. In vitro, fluvoxamine, tolfenamic acid, mefenamic acid and rofecoxib potently inhibited CYP1A2 [the 50% inhibitory concentration (IC(50)) < 10 microM]. Ethinyloestradiol, celecoxib, desogestrel and zolmitriptan were moderate (IC(50) 20-200 microM), and etodolac, ciprofloxacin, etoricoxib and gestodene weak inhibitors of CYP1A2 (IC(50) > 200 microM). At 100 microM, the other tested NSAIDs and steroids inhibited CYP1A2 less than 35%. Pre-incubation increased the inhibitory effects of rofecoxib, progesterone and desogestrel. Using the free portal plasma inhibitor concentration and the competitive inhibition model, the effect of fluvoxamine and the lack of effects of tolfenamic acid and celecoxib on tizanidine pharmacokinetics in human beings were well predicted. However, the effects of ciprofloxacin, rofecoxib and oral contraceptives were greatly underestimated even when the predictions were based on their total portal plasma concentration. Besides rofecoxib, and possibly mefenamic acid, other NSAIDs were predicted not to significantly inhibit CYP1A2 in human beings. The type of enzyme inhibition, particularly metabolism-dependent inhibition, free inhibitor concentration and accumulation of the inhibitor into the hepatocytes should be considered in extrapolations of in vitro results to human beings.

Framework for gender differences in human and animal toxicology.

Differences in exposure, anatomy, physiology, biochemistry, and behavior between males and females are a dominant theme in biology, transcending the plant and animal kingdoms. Yet differences due to sex and gender have not received adequate attention in human or animal toxicology nor always in epidemiology. Generalizations are often made about species' responses to xenobiotics, without data or consideration of female/male differences. Despite the leading role that pharmacology and drug development play in elucidating toxicokinetics, gender studies are relatively recent. Phenomenologic or clinical observations of sex differences often go unexplored, but pharmaceutical companies recognize the importance of enhanced understanding of toxicokinetics and toxicodynamics and emphasize the value of translational or integrational research--bringing laboratory findings to bedside applications and bedside questions to laboratory study. However, for many years Food and Drug Administration guidelines specifically precluded participation of females in many drug studies. Many occupational epidemiology studies, on which much of our understanding of toxic effects is based, begin by excluding women and minorities. Sex differentiation begins in the embryo under genetic and hormonal control. Changes affecting exposure, susceptibility, risk, and health continue throughout life. This paper provides a framework for analyzing the level(s) at which gender differences arise. The framework addresses exposure, toxicokinetics, toxicodynamics, and modulating influences. Men and women differ in many aspects of vulnerability to xenobiotics and other stressors, beginning with their opportunities for exposure. Toxicokinetic differences mainly involve metabolism, with few differences in absorption yet demonstrated. In addition, lifestyle, psychosocial, and hormonal factors modify the kinetics and responsiveness. Some phenomena fit the Classic Sex Hormone Paradigm in which castration (with and without hormone replacement) and administration of the opposite sex hormone demonstrate the primary regulatory role of sex hormones. Many phenomena, however, differ between males and females without showing a clear-cut relationship with the sex hormones. Since every cell both has a sex chromosome (X or Y) and is exposed to hormones, elegant techniques are just beginning to tease apart genetic from hormonal influences. Wherever possible, studies should use balanced gender and gender x age designs and should analyze data by sex and interactions, rather than simply adjusting for (discarding) gender. Power should be adequate, or lack of power (if inevitable) should be clearly stated.

Why do we need pharmacokinetic studies?

Data on the fate of sex steroids in the human organism, such as absorption, distribution, total clearance, and elimination routes, are necessary to understand and predict drug action. However, except for a few exceptions, such data are sparsely available. It is necessary to apply several approaches (descriptive, mathematic, and analytic) to describe variability and dose-response correlations, all of which are important for individualized treatment, and therefore of therapeutic relevance. In addition, such data are now unavoidable requirements for the evaluation of safety, efficacy, and quality performed by the regulatory authorities. Therefore human kinetic information is an integral part of the knowledge that forms the basis for any treatment with sex steroids.

Counter current transfer in the female adnex.

The utero-ovarian veins and lymph vessels are intimately connected with the ovarian artery in the human female and in domestic animals, with the exception of the horse and the human female. A direct, local exchange of molecules from veins and lymph vessels to arteries (counter current transfer) has been documented for this anatomic structure. Countercurrent transfer of certain inert gases (133xenon, 85krypton), of prostaglandins (PGF2 alpha), of steroid hormones (e.g. progesterone, estradiol, testosterone), and of small peptide hormones (oxytocin, relaxin) has been shown to occur in laboratory and domestic animals as well as in the human female. The transfer of the inert gases takes place within seconds. The transfer of steroid hormones and peptides is detectable within minutes while the transfer of PGF2 alpha is delayed for 20 minutes. Red blood cells or albumin are not transferred. The existence of the local transfer is postulated to be of importance for: 1) the pregnancy/non-pregnancy signal from the uterus and tube to the ovary. The signal may be a combination of a luteotrophic signal from the embryo and lack of a "non-pregnant" luteolytic signal from the endometrium, the latter probably being PGF2 alpha in some species; 2) the unilateral influence of the ovarian hormones on the function of the ovarian, tubal, and possibly uterine tissues. An active corpus luteum may create in a mono-ovulatory animal a higher progesterone level in arterial blood supplying the ipsilateral tube and ovarian interstitial tissue than on equivalent contralateral organs.

Population pharmacokinetic/pharmacodynamic modeling of cetrorelix, a novel LH-RH antagonist, and testosterone in rats and dogs.

PURPOSE: Population models for the pharmacokinetic-pharmacodynamic relationship for cetrorelix (CET), a luteinising hormone-releasing hormone (LH-RH) antagonist, and the pharmacodynamic response on testosterone production were investigated in rats and dogs. METHODS: The plasma concentrations of CET and testosterone were determined after intravenous and subcutaneous injections. The population PK/PD-models were developed using P-PHARM software. RESULTS: Absolute bioavailability of cetrorelix was 100% in rats and 97% in dogs. In rats, the pharmacokinetics was explained by a two-compartment model with saturable absorption, while a three-compartment model was used in dogs. Testosterone suppression in both species was described by a sigmoid E(max) model with maximum effect (E(max)) considered as total hormonal suppression. The duration of testosterone suppression in rats was longer at higher doses. The population elimination half-lives after iv-dose were 3.0 h in rats and 9.3 h in dogs. Population mean estimates of IC50 were 1.39 and 1.24 ng/ml in rats and dogs, respectively. CONCLUSIONS: A population pharmacokinetic model was developed to explain the dissolution rate limited absorption from the injection site. The suppression of testosterone could be described by an indirect inhibitory sigmoid E(max) model. In both species 1-2 ng/ml CET in plasma was necessary to suppress testosterone production.

Oral contraceptives: effects on glucose and lipid metabolism in insulin-dependent diabetic women and women with previous gestational diabetes. A clinical and biochemical assessment.

PIP: The obvious need for highly effective contraception in women with existing disorders of glucose metabolism has led to a search for oral contraceptive (OC) regimens for such women that are efficient but without unacceptable metabolic side effects. Recent studies have indicated that low-dose OCs can be administered to women of normal weight with previous gestational diabetes mellitus without the risk of a deterioration in glucose tolerance. The present study found that, in both women with previous gestational diabetes mellitus and normal women, triphasic OCs resulted in a significantly lower insulin response to oral glucose than the low-dose monophasic estradiol/levonorgestrel formulation. This finding suggests that the progestogen component of OCs is largely responsible for the influence of OCs on glucose homeostasis. In women of normal weight with previous gestational diabetes mellitus, there is no apparent direct association between glucose tolerance, plasma insulin levels, and insulin binding to erythrocytes and monocytes during intake of low-dose OCs; in addition, there is no adverse effect on lipid/lipoprotein levels. In women with insulin-dependent diabetes mellitus, combined OCs (estradiol-estriol/norethisterone) appear to have no adverse effects on the diabetic control; however, low-dose artificial OCs are without any influence on glycemic control in these women. Treatment with norethisterone alone appears to be an appropriate alternative to both the nonalkylated estrogen/norethisterone combinations and triphasic OCs. More longterm studies are needed regarding the effects on glucose and lipoprotein metabolism to predict the clinical significance on the occurrence of cardiovascular diseases and the deterioration of glycemic control in women with insulin-dependent diabetes and previous gestational diabetes.^ieng