Research Article
The role of estradiol in primate ovarian function
- MARY B ZELINSKI-WOOTEN, CHARLES L CHAFFIN, DIANE M DUFFY, KRISTINE SCHWINOF, RICHARD L STOUFFER
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- Published online by Cambridge University Press:
- 01 March 2000, pp. 3-23
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Two-cell, two-gonadotrophin interactions within the ovarian follicle involve stimulating theca cells with luteinizing hormone (LH) to produce androgens which enter granulosa cells where, under the influence of follicle stimulating hormone (FSH), they are aromatized to estradiol. In nonprimate species, autocrine and paracrine functions for estradiol within the follicle have been shown to mediate the trophic effects of FSH on granulosa cells resulting in proliferation, increased expression of FSH receptors, antrum formation, induction of LH receptors, and inhibition of apoptosis. The axiom that estradiol is particularly necessary for follicular growth and maturation has been routinely adopted and perpetuated for decades in discussions on the regulation of follicular function in primates. Focus on the level of estradiol in follicular fluid as an index of follicle, and hence oocyte, quality by many investigators yielded conflicting results. Nonetheless, development of ovarian stimulation protocols that employ exogenous administration of both FSH and LH for the treatment of infertility in women rely on the correlation between the growth of multiple follicles and increasing serum levels of estradiol to predict a successful outcome. Initial reports of rare conditions causing defects in follicular estradiol biosynthesis, such as with P450-17αhydroxylase/17,20 lyase deficiency, associated the disruption of follicular development with estradiol deprivation. However, the elevated levels of gonadotrophins also observed in these patients rather than the absence of intrafollicular estradiol may have led to the dysregulation of folliculogenesis. Evidence to counter the notion that follicles can only grow in an estradiol-replete environment was provided by studies of women with hypogonadal hypogonadism and of medically hypophysectomized macaques, wherein low levels of estradiol were accompanied by induction of multiple preovulatory follicles upon treatment with urinary preparations of FSH alone. Unfortunately, there are no data available from these studies on oocyte performance under conditions of low estradiol resulting from steroidogenic enzyme deficiencies or hypogonadal hypogonadism. Recent studies of steroid-depleted as well as hypogonadal women and macaques reinvestigated the hypothesis that estradiol plays a pivotal role in folliculo- and gametogenesis in primates and are discussed below.
Insulin action on the ovary
- HELEN LYALL, GWYN W GOULD
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- 01 March 2000, pp. 25-39
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Polycystic ovary syndrome (PCOS) is usually defined clinically by hyperandrogenism and anovulation. Hyperinsulinaemia and insulin resistance are prominent features both in obese and nonobese women with PCOS, the latter having been shown to be more insulin resistant and hyperinsulinaemic than age- and weight-matched normal women. There is now a substantial body of evidence implicating hyperinsulinaemia in the pathogenesis of this disorder.
The development and applications of LHRH antagonists
- M LUDWIG, R E FELBERBAUM, W KÜPKER, K DIEDRICH
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- 01 March 2000, pp. 41-56
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The menstrual cycle of the adult woman depends on the regulatory function of the hypothalamo–pituitary–gonadal axis. Hypothalamic luteinizing hormone releasing hormone (LHRH) plays the central regulatory role in this control. As early as 1932 the German scientists Hohlweg and Junkmann postulated an active sexuality centre, placed over the pituitary gland, as the organ with direct stimulatory effect on the ovaries. It was shown that the stimulatory activity of the pituitary gland depends on hypothalamic function, revealing a neural control mechanism. LHRH is a peptide composed of ten amino acids, first isolated and characterized in 1971. LHRH is secreted by neural cells of the nucleus arcuatus in the mediobasal portion of the hypothalamus. The axons of these neurones are in intimate contact with the vessels of the hypothalamo–pituitary portal system. The pulsatile release of LHRH by the hypothalamic neurones causes the gonadotrophic cells of the pituitary gland, which make up about 10% of the gland's cell mass, to release follicle stimulating hormone (FSH) and luteinizing hormone (LH), also in pulsatile fashion. FSH and LH in turn control follicular maturation and gonadal sex steroid biosynthesis. Circulating LHRH is extremely short-lived, with a plasma half-life of two to five minutes, due to rapid enzymatic degradation by peptidases which preferentially interact with the peptide bonds in position six of the molecule. This short half-life ensures that hypothalamic pulses of LHRH are recognized as single events by pituitary receptors. Conversely, continuous administration of LHRH causes a decrease of LHRH receptor density on the gonadotrophic cells of the pituitary gland, reduced LH and FSH levels, and arrest of follicular maturation and sex steroid biosynthesis. The elucidation of neuroendocrine control of the menstrual cycle in adult women based on these findings is one of the most important observations in reproductive medicine during the last three decades, and has had a major clinical impact on the treatment of hormonal disorders in gynaecology and paediatrics, infertility treatment and oncology.
Uterine gene therapy and implantation
- A M SHARKEY
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- 01 March 2000, pp. 57-71
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The endometrium undergoes cyclical changes under the influence of ovarian steroids, resulting in a tissue receptive to embryo implantation. These changes involve complex interactions between stromal cells, overlying epithelium, blood vessels and the embryo itself. For many women endometrial dysfunction is the source of considerable ill health, causing menstrual problems, pain and infertility. As the use of fertility control has become more widespread across the world, regular menstruation is the norm and abnormalities of menstruation have increased in consequence. Hormone treatments have had limited success in treating these longstanding problems, and new approaches to modulating endometrial functions such as menstruation and implantation (including contraceptives) are needed.
A hypothesis for transmission of paternal mitochondrial DNA
- JUSTIN C ST. JOHN, CHRISTOPHER J DE JONGE
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- 01 March 2000, pp. 73-85
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Since the introduction of more complex and invasive forms of assisted reproductive technologies (ART), there has been much speculation as to whether the genetic integrity of the offspring can be maintained. For example, Y microdeletions and cystic fibrosis mutations can be transmitted to the offspring following intracytoplasmic sperm injection (ICSI), as can karyotype disorders. Furthermore, speculation has arisen over the transmission of mitochondrial DNA (mtDNA) to offspring and whether maternal inheritance patterns are maintained.
Inhibins and activins and their activity in male reproductive biology
- A BAHATIQ, W LEDGER
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- 01 March 2000, pp. 87-106
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The inter-relationship between the pituitary and the gonad has long appeared too complex to be regulated solely through the mediation of the two pituitary gonadotrophins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Within the last decade, discoveries of additional regulatory mechanisms involved in the neuroendocrine control of the testis and ovary have provided new insight into the control of this sophisticated biological phenomenon. The possible contribution of inhibins and activins to the hypothalamo–pituitary–gonadal axis, and their role as paracrine regulators in the testis and ovary have received increasing attention over the years following their isolation and sequencing. This review will assess current knowledge concerning the endocrine and paracrine actions of inhibins and activins in the reproductive biology of the male, with particular attention being paid to possible cross-species differences in function.