Showing papers in "Seminars in Reproductive Medicine in 2004"

Aromatase: biologic relevance of tissue-specific expression.

Abstract: Aromatase p450 (p450arom) catalyzes the formation of estrogen in several human tissues under the control of alternatively used promoters. Each promoter is regulated by a distinct signaling pathway in a tissue- and hormone-specific manner. This article reviews these regulatory mechanisms in the ovary, adipose tissue, placenta, bone, brain, and various malignant cells. Moreover, the physiological and pathologic impacts of local estrogen biosynthesis in contrast to circulating estrogen or estrogen-responsive human tissues are discussed.

The rise in adrenal androgen biosynthesis: adrenarche.

Abstract: Adrenarche is characterized by the increase in adrenal androgen production, namely dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) that occurs around 6 years of age. These steroids are secreted by the zona reticularis (ZR) of the adrenal gland. This is associated with pubarche or the increase in androgen-dependent hair growth at the time of puberty. The increase in adrenal androgen production can be explained by the increase in the expression of DHEA-synthesizing steroidogenic enzymes in the ZR. Adrenarche is an event independent of gonadarche and is found only in humans and select nonhuman primates. Although numerous prenatal and postnatal factors are important in the onset of adrenarche, a specific adrenal cortical androgen-stimulating hormone has not been identified. Evidence also exists for a role for adrenarche in behavior, skeletal maturation, and postpubertal well-being. Adrenarche is influenced by sex and race, and some of this variation may be related to the insulin and insulin-like growth factor (IGF) signaling pathways. In addition, children with premature and exaggerated adrenarche may be predisposed to certain diseases later in life.

Regulation of gonadotropins by inhibin and activin.

Abstract: Inhibin, activin, and follistatin were first identified as gonadal hormones that could exert selective effects on follicle-stimulating hormone (FSH) secretion without affecting luteinizing hormone (LH). Although the primary source of inhibin remains the gonad, both activin and follistatin are produced in extragonadal tissues and can exert effects on FSH through an autocrine-paracrine mechanism. These proteins can effect the regulation of the gonadotropins at many levels. First, activin can directly stimulate FSH biosynthesis and release from the gonadotrope cells of the pituitary gland. Second, activin up-regulates gonadotropin-releasing hormone receptor (GnRHR) gene expression, leading to alterations in the synthesis and release of both gonadotropins in response to GnRH. Third, activin can stimulate GnRH release from GnRH neurons in the hypothalamus and thereby affect FSH and LH secretion. Both inhibin and follistatin can negatively regulate these effects by preventing activin binding to the activin receptor at the cell membrane and blocking activation of downstream signal transduction pathways. This review concentrates on the mechanisms through which inhibin, activin, and follistatin regulate the gonadotropins. We discuss the expression of inhibin/activin subunits and receptors throughout the hypothalamus and pituitary and their role in the regulation of FSH and LH. The mechanisms of inhibin and activin signaling are also reported, with particular attention to developments in our understanding of inhibin receptor action and activin-induced transcriptional regulation of the FSHbeta gene promoter. Finally, we present recent findings that other members of the transforming growth factor beta superfamily may also play an important role in transcriptional regulation of the pituitary gonadotropins.

Adrenal androgens and intracrinology.

Abstract: In postmenopausal women, all estrogens and nearly all androgens are made locally in peripheral target tissues from the inactive adrenal steroid precursor dehydroepiandrosterone (DHEA). In adult men, approximated 50% of androgens are made locally. This new section of endocrinology, which describes the local formation of sex steroids, has been named intracrinology. In fact, all the enzymes required to make androgens and estrogens are expressed in a cell-specific fashion, thus permitting local control of steroid formation and action. The local inhibition of sex steroid formation or action has shown important benefits in the treatment of hormone-sensitive cancers, including significant prolongation of survival and even curing localized disease. On the other hand, exogenous DHEA provides important advantages in postmenopausal women because it compensates for the declining secretion of DHEA by the adrenals with age. The benefits of DHEA include increased bone mineral density, muscle mass, well-being, and libido, as well as beneficial effects against skin atrophy, type 2 diabetes, and obesity.

Aromatase and endometriosis.

Abstract: Aromatase p450 (p450arom) is the key enzyme for biosynthesis of estrogen, which is an essential hormone for the establishment and growth of endometriosis. There is no detectable aromatase enzyme activity in normal endometrium; therefore, estrogen is not locally produced in endometrium. Endometriosis tissue, however, contains very high levels of aromatase enzyme, which leads to production of significant quantities of estrogen. Moreover, one of the best-known mediators of inflammation and pain, prostaglandin E (2), strikingly induces aromatase enzyme activity and formation of local estrogen in this tissue. Additionally, estrogen itself stimulates cyclo-oxygenase-2 and therefore increases the formation of prostaglandin E (2) in endometriosis. We were able to target this positive feedback cycle in endometriosis using aromatase inhibitors. In fact, pilot trials showed that aromatase inhibitors could decrease pelvic pain associated with endometriosis.

Organization of the human aromatase p450 (CYP19) gene.

Abstract: The human CYP19 (p450arom) gene is located in the 212 region on the long arm of chromosome 15 (15q212) This gene spans a region that consists of a 30 kb coding region and a 93 kb regulatory region ( approximately 123 kb total length) Its regulatory region contains at least 10 distinct promoters regulated in a tissue- or signaling pathway-specific manner The Human Genome Project data published in 2000 enabled us to accurately align these promoters within the 93 kb regulatory region of the p450arom gene Each promoter is regulated by a distinct set of regulatory sequences in DNA and transcription factors that bind to these specific sequences In most vertebrates, p450arom expression is under the control of gonad- and brain-specific promoters In humans, however, there are at least eight additional promoters that were apparently recruited throughout evolution, possibly via alterations in DNA A critical mechanism that permits the use of such a large number of promoters seems to be the extremely promiscuous nature of the common splice acceptor site because, with activation of each promoter, an untranslated first exon is spliced onto this common junction immediately upstream of the translation start site in the coding region These partially tissue-specific promoters are used in the gonads, bone, brain, vascular tissue, adipose tissue, skin, fetal liver, and placenta for estrogen biosynthesis necessary for human physiology Ovary and testis use promoter II, which is located immediately upstream of the coding region The adipose tissue in general, including adipose tissue of the disease-free breast, on the other hand, maintains low levels of aromatase expression primarily via promoter I4, which lies 73 kb upstream of the common coding region Promoters I3 and II are used only minimally in normal breast adipose tissue Promoter II and I3 activities in breast cancer tissue, however, are strikingly increased Additionally, the endothelial-type promoter I7 is also upregulated in breast cancer Therefore, breast tumor tissue takes advantage of four promoters (II, I3, I7, and I4) for aromatase expression and estrogen production The sum of p450arom mRNA species arising from these four promoters contributes significantly to elevated levels of total p450arom mRNA in breast cancer in contrast to the normal breast that uses promoter I4 Because each mRNA species contains the identical coding region regardless of the variable untranslated first exon, the encoded protein functions as the aromatase enzyme in each case

Adrenal androgens and the immune system.

Abstract: Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are the main adrenal androgens (AAs) produced in humans Production of these steroids, like that of cortisol, is under the control of hypothalamic corticotropin-releasing hormone (CRH) and pituitary ACTH Other factors, however, appear to be involved in AA secretion because there are many instances in which their circulating levels do not change in parallel to those of cortisol Apart from physiological alterations associated with fetal adrenal regression, adrenarche and aging, the main instances of divergence in AA production compared with those of corticosteroids occur when immune function is activated or is aberrant Relative reductions in DHEA and DHEAS have been noted in subjects with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), human immunodeficiency virus (HIV) and autoimmune deficiency syndrome (AIDS), sepsis, and trauma In some instances, differences in the AA responses have been linked to a clinical course The mechanisms for impairments in AA production in the absence of suppressed corticoid secretion are unclear but may involve circulating cytokines or locally released mediators from immune system cells in the adrenal gland There also is evidence that DHEA and DHEAS play a role in immune competence, displaying biological effects opposite to those of corticosteroids

The human fetal adrenal: making adrenal androgens for placental estrogens.

Abstract: During most of gestation, the fetal adrenal gland is almost solely dedicated to the production of dehydroepiandrosterone sulfate (DHEA-S). This specialized ability of the fetal adrenal is unique to primates and occurs because of a specialized fetal zone that composes the bulk of the fetal adrenal gland. Morphologically and physiologically, the human fetal adrenal (HFA) glands are remarkable organs. The glands at term are almost the size of the fetal kidney due in large part to the presence of the fetal zone, which at term produces more steroid than is normally secreted by adrenal glands of the adult. Much of the steroid released by the fetal zone is DHEA-S, which is used by the placenta to produce estrogens. Herein, we review the features of the HFA gland, including its impressive ability to synthesize large amounts of adrenal androgens for use by the placenta to produce estrogens.

Aromatase and leiomyoma of the uterus.

Abstract: In leiomyoma of the uterus, both aromatase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type I are overexpressed compared with myometrium. This suggests that leiomyoma cells convert circulating androstenedione into estrone (via aromatase), then into the active form of estrogen, estradiol (via 17beta-HSD type I). In vitro experiments and several clinical findings support the notion that in situ estrogen plays a role in leiomyoma growth under hypoestrogenemic conditions, such as natural menopause and therapy with gonadotropin-releasing hormone (GnRH) agonists. GnRH agonists abolish estrogen production both in situ in leiomyoma and in the ovary, leading to quick and profound regression of the leiomyoma. Aromatase inhibitors also inhibit estrogen synthesis in both leiomyoma and the ovary and may be used therapeutically. Certain doses of competitive aromatase inhibitors would completely inhibit estrogen production in leiomyoma, whereas ovarian production of estrogen would continue at reduced levels. This may lead to advantageous therapeutic conditions in which leiomyoma regresses without adverse symptoms related to estrogen depletion because levels of ovarian estrogen would be insufficient to support leiomyoma growth but sufficient to prevent symptoms associated with deficiency. This article discusses the potential uses of aromatase inhibitors.

Is there a receptor for dehydroepiandrosterone or dehydroepiandrosterone sulfate

Abstract: It remains unknown whether dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) have a physiological role other than serving as metabolic intermediates in androgen synthesis. Apart from intracellular metabolism, there is no convincing cellular mechanism of action for physiological concentrations of DHEA(S). Unlike other major steroids, a receptor for DHEA(S) has not been definitively isolated. This article will review the evidence supporting a receptor-dependent basis for the direct physiological effects of DHEA(S). The data supporting an intracellular receptor for DHEA(S) are relatively weak and do not allow us to determine whether DHEA(S) directly, or a metabolite of DHEA(S), acts as a direct receptor ligand. Recent data strongly support a plasma membrane receptor for DHEA, but this potential receptor is yet to be isolated. Definitive characterization of the molecular mechanism (receptor or otherwise) of DHEA(S) action is necessary before we can determine whether DHEA(S) has a biological role other than as an androgen precursor.

Inhibins in normal male physiology

Abstract: Inhibin is a dimeric glycoprotein that suppresses follicle-stimulating hormone (FSH) secretion from the pituitary Two bioactive forms of inhibin exist, inhibin A and B The availability of specific immunoassays for each of the isoforms has enabled the study of the individual inhibins and their physiological roles In the male, inhibin B is the circulating form in all species studied to date except the sheep Inhibin B is produced in the testis, principally by the Sertoli cells There are temporal changes in inhibin expression and secretion with the changing role of the Sertoli cell in immature and adult testes Variations in inhibin B production between species reflect the different patterns of maturation In the adult, inhibin B levels are positively correlated with Sertoli cell function, sperm number, and spermatogenic status and are negatively correlated with FSH It appears that the regulation of inhibin B production is mediated by a complex interaction between FSH, Sertoli cells, Leydig cells, and germ cells Inhibin may also play a role at an autocrine or paracrine level in modulating the actions of activin

Aromatase inhibitors in ovulation induction.

Abstract: The new third generation aromatase inhibitors are extremely potent and specific oral inhibitors of estrogen production. We reported the success of using aromatase inhibitors for induction of ovulation in World Health Organization (WHO) type II anovulatory patients. Promising pregnancy rates were associated with the use of aromatase inhibitors for induction of ovulation in these women. In addition, the use of aromatase inhibition in conjunction with gonadotropin injection was associated with a significant reduction in the gonadotropin dose required for optimum controlled ovarian hyperstimulation. We believe that these oral agents are efficient and safe and have many advantages compared with clomiphene citrate (CC). We propose that aromatase inhibitors will replace CC in the future as the new primary treatment for ovulation induction. In this review, we present an update on the use of aromatase inhibitors for induction of ovulation and we discuss several new areas of potential interest regarding the use of aromatase inhibitors, either alone or together with recombinant follicle-stimulating hormone (FSH) for infertility treatment. Further research in these areas may demonstrate an expanded role in assisted reproductive technologies.

Variations in adrenal androgen production among (nonhuman) primates.

Abstract: The synthesis and secretion of the adrenal androgens dehydroepiandrosterone (DHEA) and its sulfate (DS) is a phenomenon apparently unique to humans and nonhuman primates. It occurs at three life stages: in utero from the fetal zone (FZ) cells of the developing adrenal cortex, during adolescence with the onset of adrenarche and the development of the zona reticularis (ZR), and in ever decreasing amounts from the ZR with aging (adrenal senescence). Insufficient data exist to know if any single nonhuman primate exactly mirrors human adrenal androgen secretion through all three life stages, and detailed morphological, biochemical, and endocrinologic studies are required to do so. Androgen synthesis requires that cells express three key enzymes, 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17), nicotinamide-adenine dinucleotide phosphate (NADPH)-cytochrome P450 oxidoreductase (CPR), and cytochrome b5, and that they do not express 3beta-hydroxysteroid dehydrogenase (3beta-HSD). Cytochrome b5 has emerged as a particularly useful marker of androgen synthetic potential. Although a reliable index of the rate of adrenal androgen secretion, DS concentrations may not accurately reflect total adrenal androgen output because rates and routes of androgen metabolism may vary greatly among species. Based on the very limited available data, the most promising nonhuman primate models are marmosets for the human FZ, chimpanzees for human adrenarche, and macaques and baboons for mature ZR function that declines with senescence.

Overview of dehydroepiandrosterone biosynthesis

Abstract: The biosynthesis of dehydroepiandrosterone (DHEA) from cholesterol involves only two enzymes, both cytochrome P450s. The conversion of cholesterol to pregnenolone is mediated by cholesterol side-chain cleavage enzyme (CYP11A1), which is found in the mitochondria. The cleavage of pregnenolone to DHEA requires both the 17alpha-hydroxylase and 17,20-lyase activities of CYP17, which is found in the endoplasmic reticulum. These conversions require pairs of electron transfer proteins or redox partners, which are adrenodoxin and adrenodoxin reductase for CYP11A1 and cytochrome P450-oxidoreductase and cytochrome b5 for CYP17. In addition, the steroidogenic acute regulatory (StAR) protein regulates the flux of cholesterol into the biosynthetic pathway and represents the mechanism of acute regulation. Finally, in addition to possessing CYP11A1 and CYP17, it is equally important that a steroidogenic cell not contain other enzymes that drain the flux of pregnenolone to DHEA. These characteristics are illustrated by the fetal adrenal cortex and the zona reticularis, which are dedicated to the synthesis of DHEA and DHEA-sulfate.

Treatment strategies for uterine leiomyoma: the role of hormonal modulation.

Abstract: Uterine leiomyomas are the most common gynecological tumors and are a significant health concern for many women. Although the exact etiology of these tumors is unknown, epidemiological and experimental animal studies have established a role for ovarian hormones in the pathogenesis of this disease. Current treatment regimens for symptomatic tumors primarily require surgical intervention. However, a major emphasis of leiomyoma research involves understanding how hormones regulate tumor growth to target the hormonal dependence of these tumors with new therapeutic strategies. Gonadotropin-releasing hormone agonists that block hormone production and induce a hypoestrogenic milieu can be utilized as adjuvant therapy; however, these drugs do little to reduce tumor cellularity, and their negative impact on bone mineral density limits their use. Selective estrogen receptor modulators (SERMs) are nonsteroidal therapeutic agents that bind to the estrogen receptor and elicit tissue-specific estrogen agonist or antagonist effects. SERMs are effective in the treatment and prevention of breast cancer, and preclinical and clinical data suggest that these hormonal modulators may also be beneficial for the treatment of uterine leiomyomas. Continued efforts to understand the role of hormones in the development of this disease will allow the development of newer, less invasive treatment strategies, which will help minimize the negative impact of these tumors on women's health.

Molecular biology of inhibin action.

Abstract: Inhibins are dimeric glycoproteins that have primarily been studied for their role in antagonism of activin-mediated release of follicle-stimulating hormone (FSH) from gonadotropes of the anterior pituitary. As a member of the transforming growth factor beta (TGFbeta) superfamily of ligands and receptors, inhibin shares several processing and structural features with other ligands of the family. An inhibin molecule is composed of an alpha-subunit and a beta-subunit, and two isoforms have been widely investigated, inhibin A (alpha/betaA) and inhibin B (alpha/betaB). Each isoform undergoes processing from a large precursor protein to a mature 32- to 34-kDa form, depending upon the degree of glycosylation. In the absence of inhibin, for example, in ovariectomized animals or postmenopausal women, serum FSH levels rise precipitously. In unilaterally ovariectomized animals the brief loss of inhibin results in a sudden rise in FSH, which induces the remaining ovary to compensate with inhibin subunit expression in a large number of antral follicles. FSH levels are restored and the cycle continues. These studies demonstrate the need for ovarian inhibin to maintain normal gonadotropin levels. Recent studies have provided a mechanism of inhibin action that is consistent with its role in reproduction and may expand inhibin function to tissues outside the reproductive axis. Betaglycan is able to bind inhibin, and in the presence of betaglycan, the affinity of inhibin for activin receptors is increased 30-fold. Through interaction with the coreceptor, inhibin can disrupt activin interaction with its receptors and can also disrupt the interaction of activin receptors with other members of the TGFbeta superfamily, such as the bone morphogenetic proteins. These new studies provide evidence for inhibin activity in numerous organs throughout the body and for mediation of systems controlled by molecules other than activin.

Adrenal androgens and aging.

Abstract: Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are the principal C19 steroids produced by the human adrenals. Their plasma levels decline to less than 20% of their maximal value during aging. Because these steroids appear to play a role in the maintenance of immunity, musculoskeletal integrity, and cardiovascular health, age-associated declines in adrenal androgen production may contribute to decreased immune function, osteoporosis, and atherosclerosis. Production of DHEA and DHEAS has been localized to the zona reticularis (ZR) of the adrenal cortex and can be modulated by intra-adrenal or extra-adrenal modulators. Extra-adrenal modulators include corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), insulin, and transforming growth factor beta (TGF-beta). Intra-adrenal regulators include enzymes and proteins involved in the steroidogenic pathway, specifically 17,20 lyase activity and DHEA sulfotransferase (DST). The natural histories of the emergence of adrenal androgen production and the ontogeny of the ZR appear to correlate closely. In addition, aging results in a decline in adrenal androgen production, and our data suggest a parallel diminution in the area represented by the ZR. This decline in the ZR may result from apoptosis, cellular and humoral immunity, or a reduction in the replicative capacity of the cells of the ZR.

Regulation and function of inhibins in the normal menstrual cycle.

Abstract: The development of assays specific for dimeric inhibin A and inhibin B defined the distinct physiology of these two hormones in the normal menstrual cycle. Inhibin A and inhibin B expression and secretion along with their differential regulation by gonadotropins explain their unique serum patterns and their potential endocrine and ovarian autocrine-paracrine functions. There is evidence that inhibin A and inhibin B play an endocrine role in the negative regulation of follicle-stimulating hormone (FSH) in nonhuman primates and humans. However, some studies suggest that estradiol is a more important, if not the only, negative feedback regulator of FSH in women. There is also evidence from animal models that inhibins and activins play a critical role in follicle development. Future work will be necessary to define further the relative role of the inhibins, estradiol, and other autocrine-paracrine factors in these important reproductive functions.

Therapeutic potential for the selective progesterone receptor modulator asoprisnil in the treatment of leiomyomata.

Abstract: Asoprisnil is a novel selective progesterone receptor modulator that exhibits partial agonist and antagonist activities in animals and humans. It demonstrates a high degree of progesterone receptor specificity and tissue selectivity. Although asoprisnil at high doses exhibited some antiglucocorticoid activity in animal models, no antiglucocorticoid effects were observed at therapeutic doses in humans. In male rats, asoprisnil showed mixed androgenic and antiandrogenic properties. Unlike antiprogestins, asoprisnil at high doses exhibited only marginal labor-inducing activity in guinea pigs during midpregnancy and was completely ineffective in inducing preterm parturition. In nonhuman primates, asoprisnil completely eliminated menstrual cyclicity and induced endometrial atrophy. Early clinical studies of asoprisnil in healthy volunteers demonstrated a dose-dependent suppression of menstruation, irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no breakthrough bleeding. Phase 2 studies in subjects with uterine fibroids demonstrated that asoprisnil induced amenorrhea and reduced the volume of the dominant leiomyoma in a dose-dependent manner without altered basal estrogen and with virtually no clinical symptoms of estrogen deprivation. Asoprisnil seems to exhibit a direct inhibitory effect on both the endometrium and leiomyoma. In all studies to date, asoprisnil has maintained a favorable safety and tolerability profile. Thus, asoprisnil has the potential to target the major clinical symptoms of leiomyomata related to both menorrhagia and the size of the tumors and may, therefore, reduce or eliminate the need for surgery.

Models of aromatase insufficiency.

Abstract: The recent studies on humans with a defective gene that encodes aromatase p450 (p450arom) and aromatase knockout (ArKO) mice with a disrupted p450arom gene uncovered many interesting aspects of physiology. Aromatase-deficient humans and ArKO mice continue to serve as invaluable models for us to study the roles of estrogen in normal and abnormal functions of several tissues. These roles will be discussed in detail in the following review article.

Dehydroepiandrosterone replacement therapy.

Abstract: Dehydroepiandrosterone (DHEA) replacement therapy has attracted considerable attention over recent years. Significant beneficial effects of DHEA replacement have been reported in patients representing the pathophysiological model of complete DHEA deficiency, in other words, adrenal insufficiency (AI). This includes effects on well-being, energy levels, mood, and libido, which is usually impaired in AI, particularly in female patients. DHEA exerts its action mainly indirectly via downstream metabolism to sex steroids, and conversion to active androgens is likely to play a major role. In addition, DHEA has well-described neurosteroidal properties, and by exerting anti-gamma aminobutyric acid(GABA)ergic action it may have antidepressive potential. Other patient groups that may benefit from DHEA replacement are patients receiving chronic exogenous glucocorticoid treatment, which invariably leads to persistent suppression of DHEA production. In patients with systemic lupus erythematosus, DHEA has been shown to reduce disease activity and has a glucocorticoid-sparing effect. However, caution is required regarding DHEA treatment in individuals with only a relative decline in circulating DHEA levels. This particularly includes the physiological decline of DHEA and its sulfate ester observed with aging. Even the elderly maintain circulating levels of DHEA that are orders of magnitude higher than what is observed in AI. Even physiological menopause does not necessarily lead to a decrease in circulating androgens while estrogen production invariably ceases. Current evidence from randomized, controlled trials in healthy elderly persons including several cohorts of postmenopausal women does not justify the use of DHEA. However, DHEA may be a suitable option for androgen replacement in women with established androgen deficiency, for example, bilateral oophorectomy and premature menopause.

Gene expression studies in leiomyomata: new directions for research.

Abstract: Uterine leiomyomata (fibroids) are a leading women's health problem, resulting in significant morbidity and surgical intervention. As benign clonal tumors, leiomyomata also represent a target well suited to molecular analysis. Familial studies and genetic syndromes featuring leiomyomata provide compelling evidence that genetic alterations may cause fibroid development, but the specific genes involved in leiomyoma development have not been identified. Microarrays permit simultaneous comparison of the relative expression of thousands of genes, thereby highlighting specific genes that may play a role in the development of leiomyomata. Microarray studies conducted by several laboratories have identified candidate genes. However, few gene products have been confirmed with alternative experimental approaches. The objective of this article is to focus on the insights provided by microarray studies investigating leiomyoma development. Such studies suggest that although hormonal control of leiomyoma growth is observed, there are other critical pathways involved in development of the leiomyoma cell phenotype that warrant investigation. In particular, expression of extracellular matrix genes in leiomyomata is deranged and such genes represent potential novel targets for therapy.

Inhibins, activins, and follistatin in the aging female and male.

Abstract: Dimeric inhibins, activins, and follistatin (FS) were all initially characterized as reproductive endocrine hormones that regulate follicle-stimulating hormone (FSH) secretion. This model, however, has expanded under the weight of current medical evidence. Activin appears to play a central auto/paracrine role in reproductive and nonreproductive tissues. Inhibin and FS each have important counterregulatory functions in activin signaling. With reproductive aging, inhibin B declines along with the follicular pool and disturbs the dynamics of the normal menstrual cycle of midreproductive age. The loss of inhibin restraint of FSH secretion appears to be the initiating endocrine event that leads to menstrual cycle shortening and some of the hormonal unpredictability of the late reproductive years. It may also be related to the decline in fertility that occurs in reproductive aging. In men, inhibin B is an excellent marker for gonadal competence, and the decline of inhibin B with age reflects decreased gonadal reserve in both sexes. Circulating activin increases with aging, but its effect on reproduction in women and men is not clear. FS does not appear to change greatly with aging in men or women. The age-related fluctuations in this delicately balanced regulatory triad influence reproductive capacity and the sequelae of chronological aging. Elucidation of the molecular pathways responsible for the action of these hormones may allow closer integration with their current conceptual roles in aging.

Sex differences in adrenal androgens.

Abstract: The primate adrenal cortex secretes high levels of 19 carbon (C19) steroids including dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenedione. These steroids exhibit weak androgenic activity but serve as precursors for estrogens and active androgens such as testosterone. Thus, they are commonly known as adrenal androgens. Age-related changes in adrenal androgen production are well-described in humans and other primates. This article discusses the evidence for sex differences in adrenal androgen production in humans and both nonhuman primate and nonprimate animal models, which present varying degrees of sexual dimorphism in adrenal structure and function. Possible mechanisms underlying these gender differences and their relevance to human adrenocortical physiology will be discussed. Although animal and human studies have provided insight into the regulation of adrenal androgen production, the basis of the observed sex differences remains poorly understood. The putative modulation of adrenal androgen production by sex steroids merits further research, as does the possibility of gender-specific differences in adrenocortical zonation.

Apoptosis in human uterine leiomyomas.

Abstract: Human uterine leiomyomas (fibroids) are benign neoplasms that typically occur in reproductive age and perimenopausal women. These tumors pose a significant and costly health concern for numerous women throughout the world. Alternative therapies are few, with hysterectomy being the treatment of choice by many physicians. There is a growing body of evidence suggesting that the development of leiomyomas may be influenced by numerous factors including genetic, environmental, and hormonal influences resulting in a possible failure of any number of apoptotic pathways. Understanding the role apoptosis plays in the normal regression of nascent myometrial tissue and how this failure may influence leiomyoma tumor growth may provide a better understanding of how to develop effective and less invasive treatment modalities for this disease. The following review attempts to highlight what is currently known about apoptosis in leiomyomas as compared with the normal myometrium and where future research is needed.

Inhibin B in pubertal development and pubertal disorders.

Abstract: The inhibin B pubertal surge is a prominent signal of gonadal maturation in females as well as in males. In boys, it denotes the final functional maturation of Sertoli cells, which is accompanied by a progressive suppression of antimullerian hormone production. In girls it reflects the initial recruitment of preantral follicles and their evolution to the antral stage. In both the prepubertal quiescent phase and the active peripubertal phase there is a striking sexual dimorphism, inhibin B levels being significantly higher in boys than in girls, in contrast to follicle-stimulating hormone (FSH) levels. Determining inhibin B levels together with FSH levels is of considerable help for diagnosing disorders of pubertal development. In girls with central precocious precocity, inhibin B levels are in accordance with the clinical stage of maturation, by contrast to normal or low levels in the McCune-Albright syndrome. In boys with delayed puberty, inhibin B levels are very low in congenital defects of the gonadotropin-releasing hormone-FSH-testis axis, but they are normal or intermediate in constitutional delayed puberty. Together with antimullerian hormone, inhibin B is a useful marker of the presence of Sertoli cells in bilateral cryptorchidism and in the androgen insensitivity syndrome. In addition, inhibin B measurement, together with that of inhibin A, is helpful for the diagnosis and follow-up of inhibin-secreting tumors: granulosa cell tumors in girls and Sertoli cell tumors of the Peutz-Jeghers syndrome in boys. In conclusion, inhibin determination is an essential tool in the assessment of physiological development as well as in the management of pubertal disorders.

Role of inhibin in normal and high-risk pregnancy.

Abstract: Inhibins are glycoprotein hormones of which there are two molecular forms, inhibin A and inhibin B. Classically, inhibin is known to have a negative feedback effect on pituitary follicle-stimulating hormone secretion. The fetoplacental unit produces inhibin throughout pregnancy. Inhibin A is the predominant molecular form of inhibin in maternal circulation from 4 weeks of gestation. Although the precise biological function of inhibin A in pregnancy is unclear, it is evident from recent studies that inhibin A could be a better marker of placental function than human chorionic gonadotropin because of its shorter half-life. The possible clinical applications for the measurement of inhibin A in early pregnancy could be in predicting miscarriage, Down's syndrome, preeclampsia, and fetal growth restriction in the first and/or second trimester before the onset of the clinical symptoms. The source of inhibins, factors controlling inhibin production, the possible functions of inhibin, and the use of inhibin measurement in normal and high-risk pregnancy are reviewed.

The diagnostic value of inhibin in infertility evaluation.

Abstract: The fertility patient is entitled to a rapid and accurate diagnosis, a realistic assessment of the prospects for achieving pregnancy, and the timely initiation of an appropriate and effective therapy. The evaluation of ovarian reserve prior to initiation of ovarian stimulation is an important aspect of the infertility work-up of a woman requiring assisted reproductive techniques (ARTs). The ability of the ovary to respond to gonadotropin stimulation by the recruitment of a cohort of follicles is central to the success of treatment such as in vitro fertilization and intracytoplasmic sperm injection. Ovarian dysfunction, often age related, is an increasingly common cause of subfertility, and hyper- and hypogonadotropic dysovulation as well as the commoner polycystic ovarian syndrome (PCOS) are frequently encountered in fertility clinic. In cases of male-factor infertility, an ability to identify an accurate serum marker of Sertoli cell function has enhanced the diagnostic process, as previous endocrine markers such as follicle-stimulating hormone and testosterone were poor correlates of spermatogenic potential. The identification, purification, and cloning of the members of the inhibin-activin superfamily and the subsequent development of sensitive and highly specific two-site enzyme-linked immunoassays for these polypeptide hormones have provided tentative answers to many of the outstanding questions concerning the regulation of the hypothalamo-pituitary-gonadal axis. Assessment of serum levels of inhibin B appears to offer useful prognostic information about ovulatory function and predictive information about response to treatment. During very early pregnancy, especially in the presence of complications associated with ART such as multiple gestation and ovarian hyperstimulation syndrome, measurement of maternal levels of inhibin A and pro-alphaC offers a noninvasive test that can aid the counseling and management of patients.

Myomectomy and MRI-directed cryotherapy.

Abstract: The purpose of this study was to identify alternatives to hysterectomy by transabdominal interventional magnetic resonance imaging-guided cryoablation. This represents a report of a prospective institutional review board-approved protocol to study interventional magnetic resonance imaging-guided cryoablation of uterine fibroid tumors. Women were selected on the basis of symptoms that were related to uterine fibroid tumors (bleeding, uterine pain, pelvic congestion, compression symptoms) and the absence of any desire for childbearing. Magnetic resonance imaging was performed before the procedure to measure the size and number of fibroid tumors, and follow-up magnetic resonance imaging determined the reduction of the lesion. Ten patients were originally included, and nine were treated and had substantial reduction in the uterine size (average, 65% volume reduction). The primary symptoms have either improved or resolved in eight of the nine women. This is the first reported review of interventional magnetic resonance imaging-directed cryotherapy of uterine fibroid tumors. This minimally invasive therapy produced shrinkage of the tumor in nine of our first ten patients.

Potential nonhormonal therapeutics for medical treatment of leiomyomas.

Abstract: Uterine leiomyomas are a common disorder resulting in significant morbidity for women and substantial economic impact on the health care system. Current therapies include conservative surgery, hysterectomy, and hormonal therapy. Conservative surgical therapy often fails because of recurrence, and hysterectomy dramatically limits reproductive options. Radiologic therapies are associated with considerable risk of morbidity and mortality and are not likely to be compatible with reproduction. Hormonal therapies such as gonadotropin-releasing hormone (GnRH) analogues or progestins with or without estrogen are utilized by many patients, but long-term use of either is often responsible for unacceptable morbidity and hormonal therapies are not compatible with reproduction. Newer hormonal alternatives such as progesterone antagonists and selective agonists as well as "add-back" estrogen therapy in addition to GnRH analogues have been developed and show promise. However, no hormonal therapy that significantly alters estrogen and progesterone production or function is likely to be compatible with reproduction. Thus, it is important to develop novel nonhormonal therapies for medical treatment of leiomyomas. Other laboratories have evaluated pirfenidone, halofuginone, heparin, and interferon-alpha (IFN-alpha). Recent work in our laboratory suggests potential use of two additional classes of compounds, thiazolidinediones and tocopherol analogs. The rationale, evidence, and potential for the use of each of these compounds in the treatment of leiomyomas are discussed.