Transdermal Hormonal Therapy in Perimenstrual Migraine: Why, When and How?

Experimental and clinical evidence is strongly in favor of a role for estrogens in migraine. It is clear that estrogen fluctuations represent trigger factors for the attacks, while the resolution of these fluctuations (menopause) may be associated to the remission or, conversely, to the worsening of the disease. However, the exact mechanisms and mediators underlying the effects of estrogens in migraine are largely unknown. The exact mechanisms and mediators underlying the effects of estrogens in migraine are largely unknown. In this review, we summarize clinical and preclinical data that are relevant for the role of estrogens in migraine and we discuss how estrogen modulation can be exploited positively to improve hormonal-related migraine.     

Central vasopressor responses to conjugated estrogens in rats may be mediated via a renin-angiotensin system in the brain

Central effects of sex steroids on cardiovascular regulation and on behavior were investigated by injecting conjugated estrogens i.c.v. in conscious or anesthetized rats. Conjugated estrogens (0.1-10 micrograms) produced dose-related increases in pressure and behavioral excitation in all rats and drinking in some rats. Marked increases ii pressure and excitation with tonic convulsions resulting in death were produced by similar injections of conjugated estrogens (100 micrograms). Pretreatment with angiotensin I converting enzyme inhibitor or angiotensin II analog abolished both vasopressor responses and behavioral excitation in conscious rats. When rats were later anesthetized with urethane to allow recording of sympathetic nerve activity, 10 and 100 micrograms of conjugated estrogens produced dose-related vasopressor responses accompanied by corresponding increases in peripheral sympathetic nerve activity. Again, converting enzyme inhibitor or angiotensin II analog abolished the increases in both blood pressure and sympathetic nerve activity. By contrast, when conjugated estrogens were injected i.v. up to 2 mg/kg, neither blood pressure nor sympathetic outflow was affected. Collectively, our results suggest that conjugated estrogens infused centrally activate a renin-angiotensin system in the brain, which results in sympathetic hyperactivity leading to blood pressure elevation.     

Estrogens and environmental estrogens.

The natural female sex hormone estrogens binds once inside the cell to a protein receptor to form a 'ligand-hormone receptor complex'. The binding activates the hormone receptor, which triggers specific cellular processes. The activated hormone receptor then turns on specific genes, causing cellular changes that lead to responses typical of a ligand-hormone receptor complex. Estrogens (especially estradiol) bring out the feminine characteristics, control reproductive cycles and pregnancy, influence skin, bone, the cardiovascular system and immunity. Natural hormones are more potent than any of the known synthetic environmental estrogens (except drugs such as diethylstilbestrol [DES]). Estrogen production varies according to different factors (gender, age and reproductive cycles). Women produce more estrogen than men and the production is more abundant during fetal development than in the postmenopausal period. Most natural estrogens are short-lived, do not accumulate in tissue and are easily broken down in the liver. In contrast to natural estrogens, estrogenic drugs such as ethynylestradiol diethylstilbestrol (DES), synthetic environmental estrogens such as beta-hexachlorocyclohexane (beta-HCH), polychlorinated biphenyls (PCBs), o, p, p'DDT, 4-nonylphenol (NP) and phytoestrogens such as isoflavones or lignans, are more stable and remain in the body longer than natural estrogens. Because most of these compounds are lipophilic, they tend to accumulate within the fat and tissue of animals and humans. Thus, depending on the natural estrogen levels, environmental estrogens may have different influences (mimicking, blocking or cancelling out estrogen's effects) on estrogen activities.     

The depression of estrone-induced uterine growth by phenolic estrogens with oxygenated functions at positions 6 or 16: the impeded estrogens

Two small groups of steroids in the estrane series-here designated as impeded estrogens,-represent a class of compounds which differ from the majority of estrogenic substances in exerting certain unusual influences on growth of the uterus. The induction of these effects previously was considered to be peculiar to estriol. The unusual growth properties common to impeded estrogens are twofold: (a) after the threshold dosage required to initiate growth has been reached, the slope of the curve of increment of uterine weight in response to increased steroid dosage is very gradual rather than steep; (b) these compounds possess the ability to inhibit to a limited extent the uterine growth induced by estrone administered concurrently. The partial inhibition of estrone-induced growth of the uterus is confined to a critical dosage of the impeded estrogen and is overcome by increased dosage of the inhibitor. Estrone-induced growth of the vagina is not inhibited by impeded estrogens. Furthermore the simultaneous administration of impeded estrogens and testosterone does not lessen the amount of uterine growth evoked by the latter. The impeded estrogens so far encountered are 3-hydroxyestratriene derivatives possessing either a ketone group at position 6 or a hydroxyl group at position 16. Oxygenated functions at these positions in phenolic estrogens have special significance in the excitation and restraint of uterine growth unshared by similar groups at certain other sites of the estrane molecule.     

Use of magnesium silicate before gas-liquid chromatography for determination of "total estrogens" in urine during pregnancy.

The authors propose a simple, rapid, reproducible and reliable method for determination of "total estrogens" in urine during the last three months of pregnancy. The procedure consists of separation of free urinary estrogens, obtained after rapid hydrolysis, on a column of magnesium silicate. The estrogens are adsorbed on the column at acid pH and eluted by 1 M potassium hydroxide. Following extraction of the eluate by diethyl ether and formation of trimethylsilyl ether derivatives, the steroids are analysed by gas-liquid chromatography. This new procedure is used routinely in our laboratory, one assay being carried out in less than three hours. The results appear to be comparable to those obtained with classic methods. We wish to report the elimaination curves of "total estrogens" during normal pregnancies and their allowable limits.     

Effect of continuous intraventricular estrogen or catechol estrogen treatment on catecholamine turnover in various brain regions

The effect of 7-day i.v.t. administration of catechol estrogens (CE) or estrogens (5 micrograms/day) on the catecholamine turnover rate of various brain areas was examined in ovariectomized rats. Norepinephrine turnover was increased significantly in the hypothalamus and cerebral cortex by estradiol treatment but not by any CEs tested when compared to control values. However, the turnover rate of dopamine in the cerebral cortex was increased compared to control values only by the 2-hydroxyestrogens (2-hydroxyestradiol and 2-hydroxyestrone) and estradiol was without effect. Only estrogens and CEs with physiologically significant estrogen receptor binding affinities (17 beta-estradiol, moxestrol, 2-hydroxyestradiol and 4-hydroxyestradiol) decreased the turnover rate of dopamine in the corpus striatum compared to control values. Estrogens (17 alpha-estradiol and 2-hydroxyestrone) which are weak ligands for the estrogen receptor did not affect striatal dopamine turnover. In addition, body weight gain measured during estrogen treatment was reduced by CEs and estrogens which have significant estrogen receptor affinities. These results suggest that the CEs may play a role in central modulation of catecholaminergic function by estrogens either through direct actions of the catechol moiety or activation of estrogen receptors.     

The agonistic and antagonistic effects of short acting estrogens: a review

Based on a review of the literature, this paper clarifies the pharmacologic properties of shortacting estrogens and their role in physiology and medicine. Shortacting estrogens display mixed agonist-antagonistic properties when injected in saline. The mixed estrogenic function results from the rapid clearance of these compounds from target tissue. When administered by pellet implant, however, shortacting estrogens act as full agonists. Both the uterotropic and vaginotropic response patterns of these compounds are detailed. Shortacting estrogens stimulate early uterotropic responses while having little effect on true uterine growth when administered by injection in saline. Thus, they have no antagonistic action when examined by shortterm uterotropic assays, but display partial antagonism when longterm uterine growth assays are used. Previous research has suggested that shortacting estrogens would not be effectual or antagonistic if present in a continuous fashion which would result in constant or longterm occupancy of the estrogen receptor. Estradiol, however, does manifest these properties when injected. Shortacting estrogens do not act as antagonists on vaginotropic responses as they do uterotropic responses. The paper also reviews the functions of these compounds in various physiological states, including blood binding, metabolism, menstruation, and pregnancy. Finally, clinical considerations are discussed. Estriol has an apparent selective effect on vaginotropic events. It has been effective in correcting symptoms of menopause, for example. However, estriol is not believed to have a protective effect against breast cancer. When it is present in a continuous fashion, estriol acts as an estrogen, thereby ruling out such an effect.     

Exogenous estrogens and endometrial cancer

Reports in the lay press that exogenous estrogens cause endometrial cancer are unjustified with the present evidence. The epidemiologic method used to identify retrospectively an increased association of estrogens with endometrial cancer cannot prove causality. Mortality from endometrial carcinoma has not increased in this country and may actually be starting to decline.     

Attenuation of the self-renewal of transit-amplifying osteoblast progenitors in the murine bone marrow by 17 beta-estradiol

In agreement with evidence that estrogens slow the rate of bone remodeling by suppressing the production of both osteoclasts and osteoblasts, loss of estrogens leads to an increase in the number of osteoclast as well as early osteoblast progenitors (CFU-osteoblasts; CFU-OBs) in the murine bone marrow. Here we show that CFU-OBs are early transit-amplifying progenitors, i.e., dividing cells capable of limited self-renewal, and that 17 beta-estradiol acts in vivo and in vitro to attenuate their self-renewal by approximately 50%. Consistent with a direct receptor-mediated action of estrogens on early mesenchymal cell progenitors, anti-estrogen receptor-alpha (anti-ER alpha) Ab's stain a small number of marrow cells that exhibit characteristics of primitive undifferentiated cells, including a high nucleus/cytoplasm ratio and lack of lineage-specific biochemical markers; the effect of 17 beta-estradiol on CFU-OB self-renewal is absent in mice lacking ER alpha. Because both osteoblasts and the stromal/osteoblastic cells that are required for osteoclast development are derived from CFU-OBs, suppression of the self-renewal of this common progenitor may represent a key mechanism of the anti-remodeling effects of estrogens.     

Synthetic estrogen as a endocrine disruptor--diethylstilbestrol and oral contraceptives

Recently, considerable attention has been focused on certain environmental contaminants, endocrine disruptors, of industrial origin that may mimic the action of estrogen. Oral contraceptives containing ethynylestradiol, a synthetic estrogen, have been suspected to have adverse environmental effects since prenatal exposure to diethylstilbestrol, another synthetic estrogen, was reported to be associated with clear cell adenocarcinoma of the vagina in female offspring. In terms of magnitude and extent, such exposures to synthetic estrogens are now considered virtually insignificant compared with the secretion and excretion of natural estrogens from humans. However, as is the case with all other chemicals, continuous and rational risk assessment and risk management of these synthetic estrogens must be made.     

Modulation of pain by estrogens

It has become increasingly apparent that women suffer a disproportionate amount of pain during their lifetime compared to men. Over the past 15 years, a growing number of studies have suggested a variety of causes for this sex difference, from cellular to psychosocial levels of analysis. From a biological perspective, sexual differentiation of pain appears to occur similarly to sexual differentiation of other phenomena: it results in large part from organizational and activational effects of gonadal steroid hormones. The focus of this review is the activational effects of a single group of ovarian hormones, the estrogens, on pain in humans and animals. The effects of estrogens (estradiol being the most commonly examined) on experimentally induced acute pain vs. clinical pain are summarized. For clinical pain, the review is limited to a few syndromes for which there is considerable evidence for estrogenic involvement: migraine, temporomandibular disorder (TMD) and arthritis. Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain. Forging a more complete understanding of the myriad ways that estrogens can ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men.     

Intracrine mechanism of estrogen synthesis in breast cancer

It has been demonstrated that biologically active estrogens are locally produced from circulating inactive steroids in an intracrine mechanism in the breast carcinoma. The in situ production of estrogens is considered to play an important role in the proliferation of breast cancer cells, especially in the postmenopausal women. Therefore, the total blockade of this pathway may lead to an improvement in the prognosis in breast cancer patients due to the inhibition of estrogenic actions. In this review, we describe the recent studies of enzymes related to intracrine mechanism of estrogen synthesis, including aromatase, steroid sulfatase (STS), and 17beta-hydroxysteroid dehydrogenase, in human breast carcinoma tissues, and discuss the biological significance of local production of estrogens in human breast cancer.     

Effect of ampicillin on the urinary output of steroidal hormones in pregnant and non-pregnant women

Ampicillin administered for three days to four pregnant women caused a decrease in the urinary output of estrogens, pregnanediol, pregnanolone, 6-oxygenated progesterone metabolites, 17-oxosteroids, 17-oxogenic steroids, dehydroepiandrosterone (DHA), 16α-OH DHA and some of its metabolites; plasma progesterone investigated only in one of these women was also lowered. In two subjects treated during three ovulatory phases, the drug diminished the excretion of estrogens. Urinary pregnanediol and estrogens were decreased in one subject investigated during two luteal phases. In one post-menopausal woman, 14 day treatment with ampicillin produced an increase in the output of 17-oxosteroids and 17-oxogenic steroids. It is suggested that ampicillin may interfere with ovarian and placental progesterone metabolism.     

Measuring estrogens in women,men, and children: Recent advances 2012–2017

The measurement of estrogens is important for diagnosing and monitoring the health of women, men, and children. For example, for postmenopausal women or women undergoing treatment for breast cancer with aromatase inhibitors, the measurement of extremely low concentrations of estrogens in serum, especially estradiol, is problematic but essential for proper medical care. Achieving superb analytical sensitivity and specificity has been and continues to be a challenge for the clinical laboratory, but is a challenge that is being taken seriously. Focusing on publications from 2012 to 2017, this review will provide an overview of recent research in the development of methods to accurately and precisely measure estrogens, including a variety of estrogen metabolites. Additionally, the latest in clinical research involving estrogen measurement in women, men, and children will be presented to provide an update on the association of estrogens with diseases or conditions such as breast cancer, precocious puberty, infertility, and pregnancy. This research update will provide context as to why estrogen measurement is important and why laboratories are working hard to support the recommendations made by the Endocrine Society regarding estrogen measurement.     

Endocrinology of climacteric and postmenopause

Climacterium is the transition from a cyclical ovarian function with ovulation to primarily irregularities and ultimately cessation of follicular maturation with its cyclical production of estrogens and progestins. The reason is the decline in follicle count and the decreasing sensitivity of follicles to pituitary gonadotropins. In this transition a phase of elevated androgen action is found in early menopause ultimately in late menopause the ovarian androgen production decreases while the androgen production through the adrenal glands is maintained and especially prohormones which are metabolished peripherally to active androgens and estrogens are produced. In the late menopause also the adrenal androgen production is decreased. This deficiency of estrogens results in processes of deprivation and degeneration which also are dependent on the decreasing growth hormone action according to decreased production and secretion.     

Sex steroids and osteoporosis. The role of estrogens and androgens

Osteoporosis (low bone mass) depends on the peak bone mass attained and bone loss after the peak. Sex steroids (estrogens and androgens) have an impact on both processes. In this article the roles and mechanisms of estrogens and androgens are discussed in relation to clinical osteoporosis. Other hormones and hormone-like drugs, such as raloxifene, may be used to mimic the effects of natural sex steroids.     

Synthetic estrogen 17alpha-ethinyl estradiol induces pattern of uterine gene expression similar to endogenous estrogen 17beta-estradiol.

17alpha-Ethinyl estradiol is one of most widely prescribed estrogens. We compared the effects of this synthetic estrogen to those of the endogenous ovarian hormone 17beta-estradiol on the expression of four estrogen-inducible genes in the rat uterus. The genes examined include c-fos, c-jun, vascular endothelial growth factor, and creatine kinase B, which are all known to be primary responses to estrogen administration. Both estrogens induced the four target genes with similar time courses and produced the same pattern of cell-specific expression of c-fos and vascular endothelial growth factor in the uterine epithelium and stroma, respectively. Dose-response studies established that the potency and efficacy of both estrogens in the uterus were the same for all four hormone-regulated genes. These studies suggest that 17alpha-ethinyl and 17beta-estradiol produce similar if not identical patterns of gene expression in the uterus.     

Estrogen and its receptors in cancer

The involvement of estrogen and its receptors in the development of cancer has been known for years. However, the exact mechanism responsible is far from clear. The estrogen-mediated carcinogenic process is complicated by recent findings, which reveal that estrogens have multiple functions in cells, which can be either adverse or beneficial, and that the effects of estrogen may be cell-type or organ dependent. The estrogenic effect may be also greatly influenced by the state of two estrogen receptors, ERalpha and ERbeta. This review will discuss the role and function of estrogens and its receptors in cancers of three categories: (1) Breast cancer and gynecologic cancers, (2) Cancers of endocrine organs, (3) Lung cancer and cancers of digestive system. We will also review some novel treatments aiming to interfere with relevant pathways mediated by estrogens and its receptors.     

Plasma estrogens and hepatic lipase in postheparin plasma with special reference to liver disease.

Hepatic lipase and lipoprotein lipase activity in postheparin plasma, plasma total estrogens (estradiol and estrone) and triglycerides were studied in patients with various liver disorders and in a reference group. The activity of hepatic lipase was not correlated to the estrogen level either in patients or in healthy controls. Peroral administration of estradiol valeriate to healthy females resulted, however, in a selective decline in hepatic lipase activity. A slight and not significant reduction was also observed in three infertile women after administration of follitropin (FSH) for a short period. The plasma concentration of estrogens did not correlate with the levels of plasma triglycerides and the relative content of triglycerides in low density lipoproteins either in patients or the controls. Lipase inhibition mediated by increase in estrogens therefore does not seem to exaplin the hypertriglyceridemia observed in patients with liver disease.     

Structure-nongenomic neuroprotection relationship of estrogens and estrogen-derived compounds

Nongenomic estrogen signaling pathways involve extranuclear estrogen receptors or function independently from estrogen receptors. These pathways participate in neuroprotection elicited by the hormone. Additional nongenomic neuroprotective effects are attributable to antioxidant and antiinflammatory actions of estrogens. Numerous chemical modifications to afford neuroprotective compounds from estrogens while eliminating estrogenicity and maintaining or enhancing nongenomic neuroprotection have been described. This review highlights recent structure-activity studies that revealed the importance of antioxidant effects for neuroprotective estrogen analogues and derivatives.