Exogenous Sex Steroids Research Articles

Increased insulin sensitivity in young, growth hormone deficient children.

Although growth hormone (GH) has well documented insulin antagonistic effects, GH deficient adults often demonstrate insulin resistance. In young GH deficient children, increased susceptibility to hypoglycaemia might indicate increased insulin sensitivity; however, this has not been documented. We therefore determined insulin sensitivity in GH deficient and GH sufficient children. Prospective study of children undergoing insulin tolerance tests for clinical investigation of GH or cortisol secretion at a regional Paediatric Endocrine/Growth Clinic between October 1986 and December 1997. Ninety-one tests were performed in children with GH deficiency and 142 tests in children with normal GH response to insulin (peak GH > or = 20 IU/l). The standard insulin tolerance test was modified to permit frequent measurements of glucose (0, 5, 10, 15, 20, 30, 45, 60 and 90 minutes). Rate of log glucose disappearance in the first 15 minutes was calculated as a direct measure of insulin sensitivity. GH deficient children were more insulin sensitive than GH sufficient children (P = 0.004) and had lower glucose nadirs post-insulin (P = 0.005). Subgroup analysis revealed that these differences were greater in younger (< 12 years old) or pre/early pubertal children. In 14 prepubertal children, exogenous sex steroid priming resulted in lower insulin sensitivity (P < 0.05) compared to nonprimed tests. Young GH deficient children were more insulin sensitive than children with normal GH secretion. This difference attenuated with age and puberty, possibly secondary to pubertal sex steroids; however, insulin resistance as reported in GH deficient adults, was not observed in adolescents.

Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens

Precocious puberty is generally defined as the appearance of secondary sex characteristics before age 8 years in girls (or menarche before age 9 years) and before 9 years in boys. The overall incidence of sexual precocity is estimated to be 1:5000 to 1:10 000 children. The female‐to‐male ratio is ˜10:1. In addition to the psychosocial disturbances associated with precocious puberty, the premature pubertal growth spurt (with less time for prepubertal growth) and the accelerated bone maturation result in reduced adult height. Precocious puberty may be gonadotrophindependent [i.e. of central origin with premature activation of the gonadotrophin‐releasing hormone (GnRH) pulse generator] or gonadotrophin‐independent (i.e. peripheral where the GnRH pulse generator is suppressed). This can be determined by GnRH testing. The pathophysiology is the basis for different diagnostic and therapeutic strategies, i.e. in the first case a stimulated LH/FSH ratio &gt;1 and suppressive treatment with GnRH agonists (e.g. in hypothalamic hamartoma), and in the second decreased gonadotrophins and removal or suppression of the endogenous or exogenous sex steroid source (e.g. congenital adrenal hyperplasia). While several cases of gonadotrophin‐independent precocious puberty due to oestrogen exposure via the transdermal, oral, or inhalative route have been reported, no case is known with the development of subsequent secondary central precocious puberty. Food contamination with oestrogens is theoretically possible, but would most probably be sporadic and, thus, would not lead to precocious puberty. As steroid hormones in meat production are banned in the European Union, no data on the impact of environmental oestrogenic substances on human maturation are currently available. In conclusion, the risk for children to develop precocious puberty through exposure to oestrogens (or androgens) in the environment or in food is very low. Nevertheless, studies of the effects of defined environmental oestrogenic substances on the human reproductive system and on pubertal development are warranted.

Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens.

Precocious puberty is generally defined as the appearance of secondary sex characteristics before age 8 years in girls (or menarche before age 9 years) and before 9 years in boys. The overall incidence of sexual precocity is estimated to be 1:5,000 to 1:10,000 children. The female-to-male ratio is approximately 10:1. In addition to the psychosocial disturbances associated with precocious puberty, the premature pubertal growth spurt (with less time for prepubertal growth) and the accelerated bone maturation result in reduced adult height. Precocious puberty may be gonadotrophin-dependent [i.e. of central origin with premature activation of the gonadotrophin-releasing hormone (GnRH) pulse generator] or gonadotrophin-independent (i.e. peripheral where the GnRH pulse generator is suppressed). This can be determined by GnRH testing. The pathophysiology is the basis for different diagnostic and therapeutic strategies, i.e. in the first case a stimulated LH/FSH ratio >1 and suppressive treatment with GnRH agonists (e.g. in hypothalamic hamartoma), and in the second decreased gonadotrophins and removal or suppression of the endogenous or exogenous sex steroid source (e.g. congenital adrenal hyperplasia). While several cases of gonadotrophin-independent precocious puberty due to oestrogen exposure via the transdermal, oral, or inhalative route have been reported, no case is known with the development of subsequent secondary central precocious puberty. Food contamination with oestrogens is theoretically possible, but would most probably be sporadic and, thus, would not lead to precocious puberty. As steroid hormones in meat production are banned in the European Union, no data on the impact of environmental oestrogenic substances on human maturation are currently available. In conclusion, the risk for children to develop precocious puberty through exposure to oestrogens (or androgens) in the environment or in food is very low. Nevertheless, studies of the effects of defined environmental oestrogenic substances on the human reproductive system and on pubertal development are warranted.

The causes and management of endometrial breakthrough bleeding

The term breakthrough bleeding (BTB) is rather poorly defined, but essentially describes the symptom of vaginal bleeding occurring with scheduled periods of withdrawal bleeding, in the absence of pelvic pathology in women taking exogenous sex steroids, usually contraceptives or hormone-replacement therapy (HRT). It may also describe occasional bleeding in those who are predominantly experiencing amenorrhoea due to these preparations. Rather confusingly, the term is sometimes used to describe intermenstrual bleeding in women who are not taking sex steroids, when structural or other pathological causes are more likely. In the absence of such pathology intermenstrual bleeding in the normal menstrual cycle is relatively uncommon, suggesting that exogenous sex steroids can profoundly disrupt the tight regulation of endometrial vascular development, function and breakdown. Intermenstrual bleeding also occurs spontaneously in some women and it is possible that this phenomenon has similar mechanisms to that seen in sex-steroid-related breakthrough bleeding.

Advances in male hormonal contraception

New male contraceptive options are urgently needed. Safe, effective and fully reversible methods of male contraception would be useful for monogamous couples who are trying to regulate their family size. In addition, an effective male hormonal contraceptive that could be implanted or injected as a long-acting formulation every 3-6 months would be useful in countries where limiting population growth has become a public policy imperative. Male hormonal contraception is based on the same principles as traditional oestrogen-progestin female oral contraceptives. Both spermatogenesis and ovulation are dependent upon normal secretion of the pituitary gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Exogenous gonadotropin-releasing hormone (GnRH) analogues and sex steroid hormones such as testosterone CO and progestins suppress gonadotropins and spermatogenesis. Two large multicentre trials demonstrated that weekly administration of high-dosage T was very effective in suppressing gonadotropins and spermatogenesis and conferred an overall contraceptive efficacy comparable to female oral contraceptives. Studies of combination regimens of lower-dosage T plus a progestin or a GnRH analogue have demonstrated greater suppression of spermatogenesis than the World Health Organization trials of high-dosage T. Most of these male hormonal contraceptives have been associated with modest weight gain and suppression of serum high-density cholesterol (HDL) levels. In this article, we review the new developments in male hormonal contraception.

Effects of oral contraceptives on breast epithelial proliferation.

The association between oral contraceptive (OC) use and breast cancer is not fully understood. Estrogen is a known mitogen to breast epithelial cells, but there is still a controversy about the effect of added progestogens. Fine needle aspiration (FNA) biopsies were used to assess epithelial proliferation in normal breast tissue from 106 healthy premenopausal women with and without oral contraceptives. In 26 women biopsies were performed before and after 2 months of OC use. Proliferation, expressed as percentage of Ki-67/MIB-1 positive cells, was correlated to endogenous progesterone, androgenic/anabolic compounds and exogenous progestogen. We found a higher proliferation (p = 0.03) in OC users compared to non users, with mean values of 4.8% and 2.2%, respectively. There was a positive correlation between proliferation and progesterone levels in non-users and with serum levonorgestrel concentrations in women using OCs containing this progestogen (rs = 0.43, p = 0.02). Women using OCs had significantly lower serum androgen levels compared to naturally cycling women and free testosterone levels displayed an inverse relation to breast epithelial proliferation. There was a marked variation in the response to exogenous sex steroids. In certain women after 2 months of OC use, the percentage of MIB-1 positive cells was as high as 40-50%. The results add to the growing evidence that progestogens may be mitogenic in breast tissue. Increased proliferation during hormonal contraception should be regarded as an unwanted and potentially hazardous side effect. Efforts should be made to define hormonal contraceptive regimens which minimize breast epithelial proliferation and to identify those women with the most pronounced proliferative response.

Peripheral and intrauterine neutrophil function in the cow: the influence of endogenous and exogenous sex steroid hormones

It has been accepted for many years that the susceptibility of the genital tract to infection is reduced during the follicular phase compared with the luteal phase of the estrous cycle. Since the role of intrauterine neutrophils is paramount in the elimination of bacteria, it can be hypothesized that these differences in resistance to infection could be mediated by differences in uterine-derived neutrophil function. In order to test this hypothesis two groups of cows were used in this study. Group 1 cows (n=5) were studied at estrus, diestrus, after ovariectomy, after exogenous estradiol and after progesterone treatment, at which time they underwent intrauterine infusion with 1% oyster glycogen (OG) and a bacterial-free filtrate (BFF) of Actinomyces pvogenes (BFF), the latter having been recovered from a clinical case of endometritis; neutrophils were harvested by flushing from the lumen 15 to 18 h later. A peripheral blood sample was collected at the time of flushing for the assay of estradiol and progesterone for a WBC and differential count and for the harvesting of neutrophils using a Percoll single-stage discontinuous gradient. After the recovery of the cells they were re-suspended in HBSS. Group 2 (n=4) were infused with BFF during during all reproductive states as Group 1, but with OG only after ovariectomy and after treatment with progesterone and estradiol. Neutrophil chemotaxis was assessed by measuring their migration using a modified Boyden chamber and Zymogen-activated serum as a chemoattractant. Phagocytic activity was measured by determining the number of Candida albicans ingested by each neutrophil after incubation. The percentage of kill was determined using a radiometric assay in which C. albicans was labeled with L-(5- 3H) Proline. Peripheral WBC concentration was not influenced by the reproductive state of the cow; however, the mean neutrophil concentration was significantly different between the reproductive states (P<0.001) and between individual cows (P<0.001). In Group 1, there was little difference in the function of the peripheral and uterine neutrophils, and while there were differences in all 3 aspects of neutrophil function from both sources between reproductive states and individual cows, of which some were statistically significant, there was no consistent pattern. In Group 2, neutrophils recovered after the infusion of BFF had poorer function compared with those recovered after the infusion of OG. There was no consistent influence of the reproductive state or individual animal. The hypothesis that the influence of the reproductive state of the cow on the resistance of the uterus to infection is mediated by the inherent differences in either peripheral or intrauterine neutrophil function was not supported by this study.

MENSTRUAL CYCLE, CONTRACEPTION, AND PERFORMANCE

Although understanding of the unique physiology of the female athlete has increased, there are still many questions to be answered. Endogenous and exogenous female sex steroids have been shown to influence various cardiovascular, respiratory, and metabolic parameters, but these changes probably have minimal impact on the ability of most recreational athletes to participate in and enjoy their sport. Statistically significant data may or may not have clinical or performance relevance. By the same token, a statistically nonsignificant change may mean the difference between first and second place to an elite athlete. For an athlete concerned about maximizing performance, individual variability in menstrual cycle changes to various performance parameters must be considered. It is difficult to predict how accurately controlled laboratory findings from a study population apply to an individual competitor on the playing field. Athletes taking OCs for contraception or for menstrual cycle control may be able to minimize any potential side effects and performance influences by taking the lower dose triphasic pills and the newer progestins. For women with menstrual dysfunction, OCs may provide a predictable hormonal milieu for training and competition. Further scientific study is needed using large-scale, prospective, randomized clinical trials on trained athletes and accurate hormonal measurements to determine the phase of the menstrual cycle to determine short- and long-term effects of cycle phase and OCs in exercising women. As more questions continue to be answered, physicians and sport scientists will be better able to guide women not only to maximize their performance but to ensure lifelong good health.

Permanent and functional male-to-female sex reversal in d-rR strain medaka (Oryzias latipes) following egg microinjection of o,p'-DDT.

Complete sex reversal of fish is accomplished routinely in aquaculture practices by exposing fish to exogenous sex steroids during gonadal differentiation. A variety of environmental chemicals are also active at sex steroid receptors and theoretically possess the potential to alter normal sexual differentiation in fish. However, in controlled environmental chemical exposures to date, only partial alterations of fish sexual phenotype have been observed. Here we report complete, permanent, and functional male-to-female sex reversal in the Japanese medaka (Oryzias latipes, d-rR strain) after a onetime embryonic exposure to the xenoestrogen o, p'-DDT. d-rR strain medaka are strict gonochorists that possesses both sex-linked pigmentation, which distinguishes genotypic sex, and sexually dimorphic external secondary sexual characteristics, which distinguish phenotypic sex. We directly microinjected the xenoestrogen o, p'-DDT into the egg yolks of medaka at fertilization to parallel the maternal transfer of lipophilic contaminants to the embryo. At 10 weeks of age, microinjected medaka were examined for mortality and sex reversal. A calculated embryonic dose of 511 +/- 22 ng/egg o, p'-DDT (mean +/- standard error) resulted in 50% mortality. An embryonic exposure of 227 +/- 22 ng/egg o, p'-DDT resulted in 86% (6 of 7) sex reversal of genetic males to a female phenotype (XY females). XY females were distinguished by sex-linked male pigmentation accompanying female secondary sexual characteristics. Histologic examination of the gonads confirmed active ovaries in 100% of the XY females. In 10-day breeding trials in which XY females were paired with normal XY males, 50% of the XY females produced fertilized embryos; this represents a comparable breeding success rate to normal XX females. Fertilized eggs produced from XY females hatched to viable larvae. These results clearly indicate that a weakly estrogenic pesticide, o, p'-DDT, when presented during the critical period of gonadal development, can profoundly alter sexual differentiation.

Imprinting by neonatal sex steroids on the structure and function of the mature mouse prostate.

Perinatal sex-steroid exposure may result in permanent modifications in the structure and function of the prostate gland. The mechanism of such long-range alterations in hormonal sensitivity is not known. This study aimed to define the molecular requirements for neonatal sex-steroid imprinting and to investigate whether combined administration of neonatal androgens and estrogens had synergistic effects upon the mature mouse prostate. Since the interaction between endogenous and exogenous sex steroids in normal mice makes it difficult to dissociate direct from indirect effects, we used the hypogonadal (hpg) mouse, characterized by congenital androgen deficiency yet still fully responsive to exogenous androgens. Newborn mice (Days 1-2) were administered a single s.c. injection of androgens alone or in combination with an estrogen followed by testosterone-induced maximal prostate growth at maturity. The final effects were determined in 7-wk-old mice through study of ductal architecture in microdissected ventral prostates (VP) and quantitation of volume densities and diameters of prostate tissue components. A single neonatal dose of androgens, but not of estrogen, increased branching morphogenesis and VP weights at adulthood. These effects did not differ significantly between various androgens; in addition, combined androgen and estrogen treatment failed to demonstrate any synergistic effects on the prostate. We conclude that neonatal androgens induce long-range effects upon the mature VP structure as well as its secretory function and that this imprinting occurs via the androgen receptor without requiring aromatization of androgens. However, these conclusions, based on a specific treatment protocol, are confined only to the distal segment of VP, and effects of neonatal sex-steroid exposure in other regions or lobes of VP may differ.

Developmental Synergism of Steroidal Estrogens in Sex Determination

Gonadal sex in the red-eared slider turtle, Trachemys scripta, is determined by incubation temperature during embryonic development. Evidence suggests that temperature determines sex by influencing steroid hormone metabolism and/or sensitivity: steroidogenic enzyme inhibitors or exogenous sex steroid hormones and their man-made analogs override (or enhance) temperature effects on sex determination. Specifically, nonaromatizable androgens and aromatase inhibitors induce testis differentiation at female-producing temperatures, whereas aromatizable androgens and estrogens induce ovary differentiation at male-producing temperatures. Moreover, natural estrogens and temperature synergize to produce more females than would be expected if estrogens and temperature had purely additive effects on sex determination. In this study, we use sex reversal of turtle embryos incubated at a male-producing temperature to examine synergism among steroidal estrogens: estrone, 17ss-estradiol, and estriol. A low dose of 17ss-estradiol (200 ng) showed significant synergism when administered with a single low dose of estriol (10 ng). Likewise, a single low dose of estrone (250 ng) had a synergistic effect when combined with the same low dose of estriol (10 ng). We conclude that the weak natural estrogens estrone and 17ss-estradiol synergize with a low dose of the more potent estriol to reverse gonadal sex during the critical period of sexual differentiation. These results suggest that weak environmental estrogens may also synergize with stronger natural estrogens.

Developmental synergism of steroidal estrogens in sex determination.

Gonadal sex in the red-eared slider turtle, Trachemys scripta, is determined by incubation temperature during embryonic development. Evidence suggests that temperature determines sex by influencing steroid hormone metabolism and/or sensitivity: steroidogenic enzyme inhibitors or exogenous sex steroid hormones and their man-made analogs override (or enhance) temperature effects on sex determination. Specifically, nonaromatizable androgens and aromatase inhibitors induce testis differentiation at female-producing temperatures, whereas aromatizable androgens and estrogens induce ovary differentiation at male-producing temperatures. Moreover, natural estrogens and temperature synergize to produce more females than would be expected if estrogens and temperature had purely additive effects on sex determination. In this study, we use sex reversal of turtle embryos incubated at a male-producing temperature to examine synergism among steroidal estrogens: estrone, 17ss-estradiol, and estriol. A low dose of 17ss-estradiol (200 ng) showed significant synergism when administered with a single low dose of estriol (10 ng). Likewise, a single low dose of estrone (250 ng) had a synergistic effect when combined with the same low dose of estriol (10 ng). We conclude that the weak natural estrogens estrone and 17ss-estradiol synergize with a low dose of the more potent estriol to reverse gonadal sex during the critical period of sexual differentiation. These results suggest that weak environmental estrogens may also synergize with stronger natural estrogens.

Are there special considerations in the prescription of serotonin reuptake inhibitors for women?

To present information on special considerations in the prescription of selective serotonin reuptake inhibitor (SSRI) antidepressant drugs to women. Literature review and analysis of adverse drug reactions to SSRIs reported to Health Canada between 1986 and 1996. SSRIs are prescribed twice as often to women as to men. Special considerations are required of the social context in which the illness occurs, biological aspects of the illness, the effects of endogenous and exogenous sex steroids, menstruation, pregnancy, lactation, and menopause. Serious or fatal side effects are most commonly drug-drug or drug-alcohol interactions, and endocrine side effects are more common in women than men. Although SSRIs are relatively effective and safe when prescribed to women, further research is required for long-term follow-up of children exposed to these drugs in utero or during lactation. Continued study of the effects of sex steroids on pharmacodynamics and kinetics and ongoing monitoring and reporting of side effects in women is required. Special consideration of endocrine side effects and drug-drug and drug-alcohol interactions are needed for optimal safety.

Sexual dimorphism in 11 beta hydroxysteroid dehydrogenase activity and its relation to fat distribution and insulin sensitivity; a study in hypopituitary subjects.

Sexual dimorphism of 11 beta hydroxysteroid dehydrogenase activity (11 beta HSD) as measured by the urinary 11-OH/11-oxo cortisol metabolite ratio has been documented in healthy subjects. Since body composition, fat distribution and insulin sensitivity vary between the sexes we have investigated whether these factors may account for the observed difference. Studies were performed in ACTH deficient hypopituitary subjects to eliminate the effect of feedback modulation of cortisol secretion. 44 hypopituitary patients, (m:f, 32:12), median age 51 years, median weight 86 kg, on hydrocortisone and other replacement therapy as appropriate were studied. Urine 11-OH/11-oxo cortisol metabolites and serum and urine cortisone (E) and cortisol (F) were measured in relation to total cortisol metabolites and cortisol binding globulin; fat distribution was assessed by Dual Energy X-ray absorptiometry (DXA), and insulin sensitivity by homeostatic model of assessment. Cortisol bioavailability (total urine cortisol metabolites, urine free cortisol and cortisol binding globulin) was similar in both sexes. The 11-OH/11-oxo ratio was lower in females than males (median; 0.99 vs 1.3, P < 0.03) while thyroid status was similar. Females had higher percentage fat (median 47.7 vs 34.9, P < 0.01); total fat (median 39.5 vs 34.9 kg, P < 0.01), android fat (median 9.1 vs 6.6 kg, P < 0.01); gynoid fat (median; 9.9 vs 6.8 kg, P < 0.05) and lower insulin sensitivity (median 15.3 vs 30.6, P < 0.01). In all subjects, the 11-OH/11-oxo ratio was inversely related to body weight (P < 0.01), % fat (P < 0.05), total fat (P < 0.01), android fat (P < 0.01), gynoid fat, (P < 0.01) and directly correlated to insulin sensitivity, P < 0.01. Stepwise regression analysis showed gynoid fat to be the most important factor determining the 11-OH/11-oxo ratio. In 24 subjects (f:m, 8:16) on exogenous sex steroid therapy insulin sensitivity was similar but the sexual dimorphism of the 11-OH/11-oxo ratio remained unchanged (median; 1.0 vs 1.7, P < 0.05). The urine and serum F and E and their ratio (F/E) were similar in these groups. These data confirm the presence of sexual dimorphism in 11 beta-hydroxysteroid dehydrogenase activity in hypopituitary patients as described in normal individuals. This is the first in vivo evidence that this dimorphism is related to body composition. Our findings suggest that sexual dimorphism may be determined by the activity of type 1 and not type 2 11 beta-hydroxysteroid dehydrogenase.

Effects of rearing temperature on sex differentiation in the European sea bass (Dicentrarchus labrax L.)

Under culture conditions, sex ratios in the European sea bass (Dicentrarchus labrax L.) are consistently skewed in favor of males. Moreover, no heteromorphic sex chromosomes have been shown for this species. This bias towards males could be due to a possible effect of environmental factors on sex differentiation, as has already been described in other fish species. To test this hypothesis, sexually undifferentiated sea bass were reared under two different thermal regimes or two different photoperiodic regimes, resulting in four groups: Group SP = short photoperiod (9 hours light [L]:15 hours dark [D]), Group LP = long photoperiod (15 L:9 D), both reared under natural temperature (24°C, average); Group LT = low temperature (15°C), Group HT = high temperature (25°C), both reared under natural photoperiod (13.5 L:10.75 D, average). Treatments lasted 80 days, from 57 to 137 days post fertilization, coinciding with the time when gonads are more sensitive to the action of exogenous sex steroids. The resulting sex proportions were determined by periodic histological examinations of the gonads during the first 2 years of age. No females were found in group LT at any sampling, whereas in the other groups, female proportions never reached values higher than 27%. Moreover, sex differentiation in group LT was delayed with respect to the other groups, as no fish completed sex differentiation until 16.4 months of age, compared to the other groups in which some individuals completed sex differentiation at 9 months of age. In addition, growth was significantly (P > 0.05) delayed in group LT with respect to the other three experimental groups and especially marked during the first year of life. Furthermore, the low values for the gonadosomatic index (GSI), together with the decrease of the number of spermatogenic males, denote a delay in gonadal maturation with respect to the rest of the experimental groups. The results of this study suggest that temperature can play an important role in the process of sex differentiation and growth of the sea bass. However, the mechanism(s) underlying this sexual lability remain unknown. J. Exp. Zool. 281:207–216, 1998. © 1998 Wiley-Liss, Inc.

Contraception as prevention and therapy: Sex steroids and the brain

The brain is one of the specific target tissues for sex steroid hormones. Estrogens, progestins and androgens are able to induce several effects in brain areas of the central nervous system (CNS), through the binding with specific receptors. Specific receptors for gonadal steroids have been identified in the amygdala, hippocampus, basal forebrain cortex, cerebellum, locus ceruleus, midbrain rafe nuclei, glial cells, pituitary gland, hypothalamus and central gray matter. At the hypothalamic level, the principal target for sex steroids is those neurons producing the pulsatile release of the gonadotropin releasing hormone (GnRH), localized in the mediobasal hypothalamus and the arcuate nucleus. The GnRH release depends on the complex and co-ordinated interrelationships among gonadal steroids, pituitary gonadotropins and neuroactive transmitters, such as the noradrenaline, dopamine, opioid peptides (β-endorphin), acetylcholine, serotonin, γ-aminobutyrric acid, corticotropin releasing hormone and neuropeptides Y. The interplay of these control mechanisms is governed by peripheral feedback signals; as well as the input from higher brain centers they may modify the GnRH secretion. The anterior pituitary lobe is the best known target tissue for endogenous or exogenous sex steroid hormones, because it is possible to detect luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in blood, as the expression of the pituitary cells' activity. The synthesis and release of FSH and LH by the gonadotropic cells depend upon the peripheral control of gonadal hormones and the GnRH hypothalamic release.In summary, during a woman's reproductive life, the interaction between neurotransmitters, neuropeptides and gonadal hormones modulates the hypothalamo—pituitary—gonadal axis by acting selectively on the synthesis and release of GnRH and of pituitary gonadotropic hormones. The increased use of oral contraceptives in the last 30 years and, in general, of sex steroid hormone derivative therapies, has led to the study of the biochemical and metabolic properties of the different progestin molecules available in hormonal therapies by focusing attention on the interactions between estrogens and progestins in the modulation of the hypothalamo—pituitary-gonadal axis. The different kinds of estrogen and progestin molecules used in oral contraceptives inhibit the ovulatory process and may interfere with other sex steroid hormone receptors, thus exerting multiple effects in each target tissue.

Estrogen regulation of adipose tissue lipoprotein lipase—Possible mechanism of body fat distribution

OBJECTIVE: The purpose of this study was to evaluate the regulation of lipoprotein lipase activity, protein mass, and messenger ribonucleic acid by estradiol. STUDY DESIGN: Premenopausal women not taking exogenous sex steroids had transdermal 17β-estradiol and placebo patches placed in the gluteal region during the early follicular phase of the menstrual cycle. Adipose biopsies were performed from beneath the patches. Adipose tissue lipoprotein lipase activity was determined by a radiometric assay, protein mass was determined by enzyme-linked immunosorbent assay, and messenger ribonucleic acid level was determined by Northern analysis. Comparisons between the treated and placebo sides were analyzed by nonparametric statistics. RESULTS: Adipose tissue from beneath the 17β-estradiol patch had significantly decreased lipoprotein lipase activity and extracellular protein mass than did adipose tissue from beneath the placebo patch. There was no difference in lipoprotein lipase messenger ribonucleic acid levels. CONCLUSIONS: Estrogen decreases lipoprotein lipase activity by a posttranscriptional modification of protein levels. A hypothesis of sex steroid regulation of body fat distribution is proposed. (Am J Obstet Gynecol 1998;178:101-7.)

Protection by α-tocopherol but not ascorbic acid from hydrogen peroxide induced cell death in normal human breast epithelial cells in culture

α-Tocopherol and ascorbic acid have been suggested to play a role in breast cancer prevention due to their antioxidative capacity. Increased exposure to endogenous and exogenous sex steroids is a known risk factor for breast cancer. We have studied the effects of α-tocopherol and ascorbic acid on hydrogen peroxide induced cell death in sex hormone treated normal breast epithelial cells in culture. We found that α-tocopherol but not ascorbic acid alone protected the cells. The effect of α-tocopherol increased when ascorbic acid was added to the cultures. The hydrogen peroxide degradation rate decreased in cultures treated with α-tocopherol alone and in combination with ascorbic acid compared to cells grown in medium or with ascorbic acid only. Oestradiol and progesterone treatment did not influence the results. Possible beneficial effects of combining various antioxidants, endogenous as well as exogenous, on human breast tissue need to be investigated further both in vivo and in vitro.

Neutrophil migration into the uterine lumen of the cow: The influence of endogenous and exogenous sex steroid hormones using two intrauterine chemoattractants

Neutrophil migration into the uterine lumen in response to the intrauterine infusion of both an oyster glycogen suspension and a bacteria-free filtrate obtained after incubation of Actinomyces pyogenes in cooked meat medium was studied in 4 cows at estrus (Day 0) and at diestrus (Day 10). In addition, the same chemoattractants were used in 5 other cows following bilateral ovariectomy and after parenteral treatment with exogenous estradiol 17β and progesterone in oil. Large numbers of cells (average viability >85%, purity 95%) were obtained with both chemoattractants. In cyclic and bilaterally ovariectomized cows bacteria-free filtrate produced a greater migratory response than oyster glycogen, and the differences were significant (P < 0.01 and P < 0.002, respectively). On Day 10 of the estrous cycle a higher number of neutrophils was recovered than on Day 0 following infusion of oyster glycogen and bacteria-free filtrate, and again the differences were significant (P < 0.003 and P < 0.001, respectively). Following treatment of ovariectomized cows with estradiol and progesterone, greater response was observed for progesterone than for estradiol after oyster glycogen and bacteria-free filtrate treatment with significant differences (P < 0.002 and P < 0.003, respectively). Both chemoattractants produced adequate numbers of viable neutrophils suitable for subsequent evaluation of their function in vitro. The increased neutrophil response induced by progesterone, both in normal cyclic cows and after ovariectomy following progesterone treatment, may be a compensatory one due to reduced neutrophil phagocytosis and bactericidal activity or to the suppression of other uterine defense mechanisms, since this response is inconsistent with the long-recognized observation that the uterus of the cow is more susceptible to infection in diestrus than in estrus.

Endometrial responses to hormone replacement therapy: the bleeding pattern

Little information is available concerning the response of the endometrium to exogenous sex steroid therapy, particularly in the post-menopausal state. In this study we examined the variability of the bleeding pattern in 103 post-menopausal women receiving cyclical sequential combined hormone replacement therapy (HRT) over 6 months. All patients kept menstrual diary cards to record the onset, duration and subjective assessment of the severity of bleeding. We defined a cycle as starting from the commencement of treatment till the day of onset of bleeding. Two groups were identified amongst 99 women who experienced bleeding: those with a mean cycle length of 29 or more days (late bleeders, n = 50) and those with shorter mean cycle length (early bleeders, n = 49). The former were characterized by less variability in cycle length and bleeding that was of shorter duration. Four women experienced no bleeding. There were no significant differences between the two groups in age, year since the menopause, weight, height, body mass index (BMI), parity, or in the previous use of HRT. The only significant difference was in their smoking habits. This suggests a possible link of a hypo-oestrogenic state to poor cycle control.