The Reproductive System at a Glance E-Book

Linda J. Heffner

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: At a Glance
• Sprache: Englisch

Seitenzahl: 373

Veröffentlichungsjahr: 2014

Beschreibung

The Reproductive System at a Glance is a comprehensive guide to normal reproductive biology and associated pathophysiology in both sexes. Concise, easy to read, and clearly structured, the double-page spreads progress from basic science to clinical abnormalities, and covers endocrine production and action, within one short volume. Chapters on disorders summarise epidemiology, pathophysiology, diagnosis and treatment. This new edition of The Reproductive System at a Glance: * Is fully revised and updated throughout to reflect recent developments in practice * Now features histological and pathological slides to complement the "at a glance" style explanatory illustrations * Now features radiologic studies to supplement the text in selected chapters * Contains more detailed coverage of maternal adaptations to pregnancy * Includes a companion website at www.ataglanceseries.com/reproduction featuring self-assessment multiple choice questions, bonus single answer questions and flashcards The Reproductive System at a Glance is an ideal guide for students studying both endocrine and reproductive subjects, and teaches the foundation concepts for the obstetrics and gynaecology rotation, helping health professionals and students achieve a broad and practical understanding of the topic.

Leseprobe

Table of Contents

Website ad

Title page

Copyright page

Preface

Contributors

Table and figure acknowledgements

1 The pituitary gland and gonadotropins

2 Steroid hormone biosynthesis

3 Steroid hormone mechanism of action and metabolism

4 Reproductive genetics

5 Gonadal development in the embryo

6 Phenotypic sex differentiation

8 Microscopic anatomy of the male reproductive tract

11 Puberty in boys

12 Puberty in girls

13 Male reproductive physiology

16 Fertilization and the establishment of pregnancy

18 The protein hormones of pregnancy

19 The steroid hormones of pregnancy

26 Abnormalities of male sexual differentiation and development

27 Abnormalitites of female sexual differentialtion and development

32 Hyperprolactinemia

35 Multifetal pregnancy

39 Benign and malignant diseases of the breast

41 Diseases of the prostate

42 Ovarian neoplasms

44 Cervical cancer

46 Sexually transmitted diseases of bacterial origin

About the companion website

Part 1: Normal human reproduction

1: The pituitary gland and gonadotropins

Pituitary structure and function

Structure of LH and FSH

Regulation of FSH and LH

Mechanism of action of gonadotropins

2: Steroid hormone biosynthesis

Cholesterol and the steroid production pathway

Sites of production

3: Steroid hormone mechanism of action and metabolism

Mechanisms of steroid action

Agonists and antagonists

Steroids in the circulation

Steroid metabolism

Steroid excretion

4: Reproductive genetics

Chromosomes

Mitosis and meiosis

Non-disjunction

Imprinting

5: Gonadal development in the embryo

Role of sex chromatin in reproductive development

Gonadal differentiation

6: Phenotypic sex differentiation

Internal genitalia

External genitalia

7: Gross anatomy of the male reproductive tract

Testes and epididymis

Vas (ductus) deferens and seminal vesicles

Prostate gland

Penis

8: Microscopic anatomy of the male reproductive tract

Testes

Epididymis and vas (ductus) deferens

Seminal vesicles

Prostate gland

Penis

9: Gross anatomy of the female reproductive tract

Ovaries

Fallopian tubes

Uterus

Vagina

Vulva

10: Microscopic anatomy of the female reproductive tract

Ovary

Fallopian tube

Uterus

Cervix and vagina

11: Puberty in boys

Physical changes of puberty

Adrenarche

Testicular maturation

Secondary sexual characteristics

Somatic growth

12: Puberty in girls

Physical changes of puberty

Adrenarche

Breast development (thelarche)

Secondary sexual characteristics

Somatic growth

Menarche

13: Male reproductive physiology

Erection, emission and ejaculation

Hormonal control of spermatogenesis

Leydig cell function

Regulation of gonadotropin secretion in males

14: The menstrual cycle

Follicular phase

Ovulatory phase

Luteal phase

Menstrual phase

15: Human sexual response

Phases of the sexual response

Male sexual response

Female sexual response

16: Fertilization and the establishment of pregnancy

The egg

The sperm

Fertilization

Establishment of pregnancy

17: Placental structure and function

Placental morphology

Placental immunology

Placental function

18: The protein hormones of pregnancy

Placental production of protein hormones

Human chorionic gonadotropin

Human placental lactogen

Other hormones

Maternal production of protein hormones

19: The steroid hormones of pregnancy

Progesterone

Estrogens

Fetal adrenal physiology

Maternal adrenal function and salt metabolism

20: Maternal adaptations to pregnancy: I

Cardiovascular system

Respiratory system

Kidney and urinary tract

Hematologic system

Skin

21: Maternal adaptations to pregnancy: II

Thyroid gland

Gastrointestinal tract

Nutritional requirements of pregnancy

Immune system

22: Labor

Phases of labor

Initiation of labor

23: The breast and lactation

Development of the breast

Milk formation

Regulation of milk production

The lactation reflex

24: Menopause

Physiology of menopause

Signs and symptoms

25: Contraception

“Natural” family planning

Barrier methods

Spermicides

Intrauterine devices

Hormonal contraception

Sterilization

Part 2: Human reproductive disorders

26: Abnormalities of male sexual differentiation and development

Cryptorchidism

Hypospadias

Congenital bilateral absence of the vas deferens

Microorchidism

Pseudohermaphroditism

27: Abnormalities of female sexual differentiation and development

Structural anomalies

Exposure to diethylstilbestrol

Congenital adrenal hyperplasia

Turner syndrome

28: Precocious puberty

True or complete precocious puberty

Incomplete isosexual precocity

Iatrogenic sexual precocity

Virilizing precocious puberty in girls

Feminizing precocious puberty in boys

29: Delayed or absent puberty

Constitutional pubertal delay

Hypogonadotropic hypogonadism

Hypergonadotropic hypogonadism

30: Primary amenorrhea

Etiologies of primary amenorrhea

31: Secondary amenorrhea

32: Hyperprolactinemia

Regulation of prolactin secretion

Physiologic hyperprolactinemia

Pharmacologic hyperprolactinemia

Pathologic hyperprolactinemia

Galactorrhea

33: Sexual dysfunction

Sexual desire disorders

Erectile dysfunction (impotence)

Premature ejaculation

Retrograde ejaculation

Dyspareunia

Vaginismus

34: Infertility

Oocyte abnormalities

Female anatomic abnormalities

Male factors

Implantation abnormalities

Other factors

Evaluation and treatment of infertility

35: Multifetal pregnancy

Biology of monozygotic twinning

Etiology of dizygotic twins

Pregnancy risks with multiple gestations

36: Spontaneous pregnancy loss

Ectopic pregnancy

Miscarriage

Recurrent pregnancy loss

Stillbirth

37: Labor abnormalities

Preterm labor

Postterm pregnancy

Placental abnormalities

Abnormal fetal lie and presentation

38: Pre-eclampsia

Clinical spectrum of pre-eclampsia

Potential mechanisms in pre-eclampsia pathogenesis

39: Benign and malignant diseases of the breast

Common benign breast diseases

Breast cancer

Epidemiology of breast cancer

Familial breast cancer

Molecular biology of sporadic (nonfamilial) breast cancer

40: Testicular tumors

Epidemiology of GCT

Molecular biology of GCT

41: Diseases of the prostate

Benign prostatic hyperplasia

Prostate cancer

42: Ovarian neoplasms

Benign neoplasms of the ovary

Ovarian cancers

Epidemiology of epithelial ovarian cancer

Familial ovarian cancer

Pathogenesis of nonfamilial epithelial ovarian cancer

Other ovarian malignancies

43: Endometrial cancer

Epidemiology of endometrial cancer

Steroid hormones and endometrial cancer

Molecular biology of endometrial cancer

Endometrial hyperplasia

44: Cervical cancer

Epidemiology of cervical cancer

Pathogenesis of squamous cell neoplasia of the cervix

Screening tests for cervical cancer

Prophylactic HPV vaccination

Cervical adenocarcinoma

45: Genetic imprinting and reproductive tract tumors

Imprinting

Gestational trophoblastic disease

Dermoid tumors

GCTs of the testis

46: Sexually transmitted diseases of bacterial origin

Gonorrhea

Chlamydia

47: Sexually transmitted diseases of viral origin

Human papillomavirus

Herpes simplex virus

48: The special cases of syphilis and human immunodeficiency virus

Syphilis

Human immunodeficiency virus

Index

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This edition first published 2014 © 2014 by John Wiley & Sons, Ltd.

Third and Second editions published 2010; 2006 © 2010; 2006 by Linda J. Heffner and Danny J. Schust

First edition published 2001 © 2001 by John Wiley & Sons Ltd.

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Library of Congress Cataloging-in-Publication Data

Heffner, Linda J., author.

The reproductive system at a glance / Linda J. Heffner, Danny J. Schust. – Fourth edition.

p. ; cm. – (At a glance series)

Includes bibliographical references and index.

ISBN 978-1-118-60703-9 (pbk. : alk. paper)

I. Schust, Danny J., author. II. Title. III. Series: At a glance series (Oxford, England)

[DNLM: 1. Reproduction–physiology. 2. Reproductive Physiological Processes. 3. Genital Diseases, Female. 4. Genital Diseases, Male. 5. Pregnancy Complications. 6. Sexually Transmitted Diseases. WQ 205]

QP251

612.6–dc23

2014000047

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover image: iStock/ © Ugurhan Betin

Cover design by Andy Meaden (Meaden Creative)

Preface

Now in its fourth edition, The Reproductive System at a Glance is a comprehensive, easy-to-use collation of all the pertinent information on human reproductive processes and their diseases.

The most notable change between this edition and the last is the inclusion of an expanded supplementary material section. This includes multiple choice and short answer questions with detailed answers for each chapter. These questions are designed to help the student/reader determine if he or she has understood the important concepts. New material has been added to expand on normal maternal physiology in pregnancy and several new figures include pathology or radiologic images. All chapters and figures have been updated where new information is available.

The book remains divided into two parts. Part 1, which consists of 25 chapters, covers the normal human reproductive tract, continuing on through puberty with the resulting mature male and female anatomy and physiology and finally, procreation, pregnancy and menopause. Part 2, which consists of 23 chapters, covers the pathophysiology of anatomic, physiologic and psychologic disorders that interfere with normal reproductive function or health. Seven of these chapters are devoted to the more common malignancies that involve the reproductive organs.

Like its predecessor and the other books in this series, The Reproductive System at a Glance is written so that each topic is confined to a discrete vignette with appropriate illustrations or tables in a double page format. In Part 2, each topic also follows a standard format of a description of the disorder followed by its epidemiology, pathophysiology and, whenever it aids in understanding the disorder, a brief description of the commonly used treatments.

Revising a book, while easier than writing the original, remains a major undertaking to which many people contributed. We would like to thank Drs. Elizabeth Stier and David Wang for the helpful reviews on the chapters on human papillomavirus and cervical cancer, and male reproductive disorders, respectively. We would also like to thank the Obstetrics and Gynecology and Women's Health residents at the University of Missouri–Columbia for their invaluable help in creating the MCQ study guide questions for this text and Drs. A.J. Enciso, Taylor Hahn, Greg Blair and Megan Morman for help in fashioning MCQ answers and short answer questions and answers.

Finally, books never appear in print or on bookshelves without publishers. We would like to thank Elizabeth Johnston, Andrew Hallam and Karen Moore at Wiley Blackwell and also Jan East for assistance in producing this new edition. David Gardner was invaluable in revising old and drawing new figures.

Linda J. Heffner

Danny J. Schust

Boston and Columbia, 2013

Contributors

Gregory Blair, MD

Angel J. Enciso, MD

Taylor A. Hahn, MD

Megan M. Morman, MD

All at University of Missouri School of Medicine

Columbia, MO, USA

Table and figure acknowledgements

The following figures and tables have been redrawn from the originals and were used with permission of the publishers. Every effort has been made by the authors to contact all copyright holders to obtain their permission to reproduce copyright material. However, if any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the earliest opportunity.

1 The pituitary gland and gonadotropins

Figure 1.1(a): Braunstein G (1989) Placental hormones, hormonal preparation for and control of parturition, and hormonal diagnosis of pregnancy. In: Endocrinology (ed. LJ deGroot), p.2045. Elsevier, Philadelphia.

Figure 1.1(b): Halvorsen LM, Chin WW (1999) Gonadotropic hormones: biosynthesis, secretion, receptors, and action. In: Reproductive Endocrinology (eds SSC Yen, RB Jaffe, RL Barbieri), p.92. Elsevier, Philadelphia.

2 Steroid hormone biosynthesis

Figure 2.2: Yeh J, Adashi EY (1999) The ovarian life cycle. In: Reproductive Endocrinology (eds SSC Yen, RB Jaffe, RL Barbieri), p.168. Elsevier, Philadelphia.

3 Steroid hormone mechanism of action and metabolism

Figure 3.1: O'Malley BW, Strott CA (1999) Steroid hormones: metabolism and mechanism of action. In: Reproductive Endocrinology (eds SSC Yen, RB Jaffe, RL Barbieri), p.124. Elsevier, Philadelphia.

4 Reproductive genetics

Figure 4.1: Morton CC, Miron P (1999) Cytogenetics. In: Reproductive Endocrinology (eds SSC Yen, RB Jaffe, RL Barbieri), p.337. Elsevier, Philadelphia.

5 Gonadal development in the embryo

Figure 5.1: Morton CC, Miron P (1999) Cytogenetics. Adapted from Reproductive Endocrinology (eds SSC Yen, RB Jaffe, RL Barbieri), p.337. Elsevier, Philadelphia.

Figure 5.2: Williams PL, Wendell – Smith CP, Treadgold S (1966) Basic Human Embryology, p.76. Lippincott Williams & Wilkins, Baltimore.

6 Phenotypic sex differentiation

Figure 6.1: Blainsky BI (1970) An Introduction to Embryology, 3rd edn, p.497. Elsevier, Philadelphia.

Figure 6.2: Williams PL, Wendell – Smith CP, Treadgold S (1966) Basic Human Embryology, p.78. Lippincott Williams & Wilkins, Baltimore.

8 Microscopic anatomy of the male reproductive tract

Figure 8.1: Bloom W, Fawcett DW (1969) A Textbook of Histology, 9th edn, p.688. Saunders/Elsevier.

11 Puberty in boys

Figure 11.1: Marshall WA, Tanner JM (1970) Variations in pattern of pubertal changes in boys. Arch Dis Child 45: 13–23.

12 Puberty in girls

Figure 12.1: Marshall WA, Tanner JM (1969) Variations in pattern of pubertal changes in girls. Arch Dis Child 44: 291–301.

13 Male reproductive physiology

Figure 13.1(a): Jordan GH (1999) Erectile function and dysfunction. Postgrad Med 105: 133.

Figure 13.1(b): Guiliano FA, Rampin O, Benoit G, Jardin A (1995) Neural control of penile erection. Urol Clin North Am 22: 748.

16 Fertilization and the establishment of pregnancy

Figure 16.1: Alberts B, Bray D, Lewis J et al. (1994) Molecular Biology of the Cell, p.1031. Garland Science/Taylor and Francis, New York.

18 The protein hormones of pregnancy

Figure 18.1(a): Yen SSC (1989) Endocrinology of pregnancy. In: Maternal–Fetal Medicine (eds RK Creasy, R Resnik), 2nd edn, p.385. Elsevier, Philadelphia.

Figure 18.1(b): Jaffe RB, (1999) Neuroendocrine-metabolic regulation of pregnancy. In: Reproductive Endocrinology (eds SSC Yen, RB Jaffe, RL Barbieri), p.767. Elsevier, Philadelphia.

Figure 18.2: Liu JH, Rebar RW (1999) Endocrinology of pregnancy. In: Maternal–Fetal Medicine (eds RK Creasy, R Resnik), 2nd edn, p.386. Elsevier, Philadelphia.

19 The steroid hormones of pregnancy

Figure 19.1: Friesen HG, Cowden EA (1989) Lactation and galactorrhea. In: Endocrinology (ed. LJ deGroot), 2nd edn, p.2076. Elsevier.

Figure 19.2: Yen SSC (1989) Endocrinology of pregnancy. In: Maternal–Fetal Medicine (eds RK Creasy, R Resnik), 2nd edn, p.377, 380, 382. Elsevier.

26 Abnormalities of male sexual differentiation and development

Figure 26.1: Williams PL, Wendell – Smith CP, Treadgold S (1996) Basic Human Embryology, p.81. Lippincott Williams & Wilkins, Baltimore.

Table 26.1: Griffin JE. (1992) Androgen resistance – the clinical and molecular spectrum. N Eng J Med 326: 612.

27 Abnormalitites of female sexual differentialtion and development

Figure 27.1: Williams, PL, Wendell – Smith CP, Treadgold S (1966) Basic Human Embryology, p.81. Lippincott Williams & Wilkins, Baltimore.

32 Hyperprolactinemia

Figure 32.1: Yen SCC, Jaffe RB (1999) Prolactin in human reproduction. In: Reproductive Endocrinology (eds SCC Yen, RB Jaffe, RL Barbieri), p.261. Elsevier.

35 Multifetal pregnancy

Figure 35.1: FitzGerald MJT, FitzGerald M (1994) Human Embryology, p.51. Ballière Tindall/Elsevier.

39 Benign and malignant diseases of the breast

Table 39.1: Marchant DJ (1997) Risk factors in breast disease (ed. DJ Marchant), pp.116, 119. Elsevier.

41 Diseases of the prostate

Figure 41.1(a): Kirby R, Christmas T (1993) Anatomy, Embryology and Histopathology in Benign Prostatic Hypertrophy, p.18. Elsevier.

Figure 41.1(b): Lepor H, Lawson RK, (1993) Prostate Diseases, p.45. Elsevier.

42 Ovarian neoplasms

Table 42.1: DiSaia PJ, Creasman RK (1997) Epithelial ovarian cancer. In: Clinical Gynecologic Oncology, 5th edn, p.283. Elsevier.

44 Cervical cancer

Figure 44.2: Coleman DV, Evans DMD (1998) Biopsy Pathology and Cytology of the Cervix. CRC Press/Taylor and Francis.

46 Sexually transmitted diseases of bacterial origin

Figure 46.1: Diallabetta G, Hook EW, III (1987) Gonococcal infections. Infect Dis Clin N Amer 1: 1,28.

Figure 46.2: Batteiger BE, Jones RB (1987) Chlamydial infections. Infect Dis Clin N Amer 1: 1,58.

About the companion website

Don't forget to visit the companion website for this book:

www.ataglanceseries.com/reproduction

There you will find valuable material designed to enhance your learning, including:

FlashcardsInteractive MCQs from bookInteractive SAQs

Scan this QR code to visit the companion website:

1

The pituitary gland and gonadotropins

Pituitary structure and function

There are three lobes to the pituitary gland (hypophysis): the anterior lobe, the posterior lobe and the pars intermedia, a small intermediate structure lying between the anterior and posterior lobe that is actually a subdivision of the anterior lobe.

The pituitary is connected to the brain via a small branch of tissue known as the pituitary stalk or infundibulum. The posterior pituitary serves mainly as a storage site for two hormones produced in the hypothalamus: oxytocin and arginine vasopressin (also known as antidiuretic hormone, ADH). In contrast, the anterior pituitary produces tropic hormones under the regulatory control of the hypothalamus. This control is mediated by neuroendocrine signals from the hypothalamus that travel through rich vascular connections surrounding the pituitary stalk. Blood flowing through this highly vascular plexus delivers signals to the anterior pituitary gland, regulating production and release of its protein products.

There are five cell types in the anterior pituitary that are associated with tropic hormone production: gonadotropes, lactotropes, somatotropes, thyrotropes and corticotropes. These specific cells are responsible for production and secretion of: follicle-stimulating hormone (FSH) and luteinizing hormone (LH); prolactin; growth hormone; thyroid-stimulating hormone (TSH); and adrenocorticotropic hormone (ACTH), respectively. The thyrotropes and gonadotropes closely resemble each other histologically because their secretory products, LH, FSH and TSH, are all glycoprotein hormones that stain with carbohydrate-sensitive reagents. LH and FSH are produced by a single cell type, allowing coupled secretion and regulation by a single releasing factor.

Control of pituitary gland activity comes largely from the hypothalamus with important direct modulation by feedback mechanisms. The hypothalamic nuclei associated with reproduction include the supraoptic, paraventricular, arcuate, ventromedial and suprachiasmatic nuclei. Neurons in two less well-defined areas, the medial anterior hypothalamus and the medial preoptic areas, are also involved. The magnocellular (large) neurons that originate in the supraoptic and paraventricular nuclei project into the posterior pituitary and produce the hormones vasopressin and oxytocin. The parvocellular (small) neurons found in the paraventricular, arcuate and ventromedial nuclei and the periventricular and medial preoptic areas produce regulatory peptides that control the tropic hormones produced by the anterior pituitary.

Those cells in the hypothalamic nuclei that regulate the pituitary have several functions. They receive signals from higher centers in the brain, generate neural signals of their own and have neuroendocrine capabilities. The higher areas of the brain that connect to the hypothalamic nuclei involved with reproduction are the locus ceruleus, the medulla and pons, the midbrain raphe, the olfactory bulb, the limbic system (amygdala and hippocampus), the piriform cortex and the retina. Endogenous opioids also influence hypothalamic function.

The neuroendocrine signals generated within the hypothalamus are mediated by peptide-releasing factors that travel through the hypothalamic–pituitary portal system to their site of action in the pituitary gland. Gonadotropin-releasing hormone (GnRH) is the key tropic hormone for regulating gonadotrope cell function and hence, reproduction. A key neural signal in human reproduction arises from what is known as the GnRH pulse generator. The mechanism by which pulsatile GnRH release controls gonadotropin synthesis and secretion remains poorly defined. At baseline, GnRH secretes from the hypothalamus in pulses at a frequency of approximately one pulse per hour. GnRH pulse frequency is most rapid in the follicular phase, slightly slower in the early luteal phase and slowest in the late luteal phase of the female menstrual cycle. In general, rapid pulse frequencies favor LH secretion and slower pulse frequencies favor FSH release. The relationship between pulse frequency and LH and FSH secretion appears to exist in both women and men. Continuous GnRH release inhibits gonadotrope function. This is the basis for the downregulating activities of long-acting exogenous GnRH agonists and antagonists.

Thyrotropin-releasing hormone (TRH) and prolactin inhibitory factor (PIF) also have roles in reproductive regulation. Those hypothalamic neuroendocrine peptides that control growth hormone (GH) and ACTH secretion are less directly related to reproduction.

Structure of LH and FSH

LH, FSH and TSH are structurally similar. They are formed by two distinct, noncovalently bound protein subunits called α and β. The pregnancy-specific gonadotropin, human chorionic gonadotropin (hCG), is a fourth glycoprotein formed of α and β chains. The α subunit for all four hormones is identical. The β subunit of each hormone differs, conferring functional specificity on each αβ dimer (Fig. 1.1a and b). The β chains for LH and hCG are the most similar with 82% homology. Carbohydrate side chains on both the α and β chains of LH, hCG and FSH add to structural specificity. The carbohydrate chains also influence metabolic clearance rates for the glycoprotein hormones. This effect is most dramatic with the hCG molecule. The β chain of hCG has a 24 amino acid extension at its C terminus that contains four O-linked polysaccharides. This sugar-laden “tail” dramatically slows the clearance of hCG. By prolonging its half-life, the effects of small amounts of this glycoprotein are dramatically enhanced. This characteristic is very important in early pregnancy recognition and maintenance (Chapters 16 and 18).

Regulation of FSH and LH

The biosynthesis and secretion of FSH and LH are tightly controlled within the reproductive cycle. There are multiple ways in which FSH and LH can be regulated, including alterations in gene transcription, mRNA stabilization, rate of protein subunit synthesis, posttranslational glycosylation and changes in the number of gonadotropin-secreting cells.

Gonadal steroids exert negative feedback control over FSH and LH synthesis and secretion. Estrogen, androgen and progesterone receptors are present in the gonadotropin-secreting cells of the pituitary and in some neurons in the hypothalamus. In the pituitary, the gonadal steroids appear to affect the transcription rate of the genes coding for FSH-β, LH-β and the common α subunit. While there is some evidence that steroids can act at the level of the hypothalamic pulse generator, gonadal steroid hormone receptors do not appear to be present in the GnRH-containing cells of the arcuate nucleus.

There is one important exception to the generally inhibitory effect of gonadal steroids on gonadotrope function. In certain situations, estrogen exerts positive feedback on gonadotropin secretion. This is critical to produce the midcycle LH surge in women (Chapter 14) and requires a sustained (>48 h) elevation in circulating estradiol. Estrogen-induced stimulation involves both increased gonadotropin gene expression in the pituitary and alterations in GnRH pulse frequency in the hypothalamus.

Inhibin and activin are closely related peptides produced by the ovary, testes, pituitary gland and placenta that influence gonadotrope function. As suggested by their names, inhibin decreases gonadotrope function and activin stimulates it. Inhibin and activin are formed from common α and β subunits. Inhibin is formed of one α subunit linked to either of two highly homologous β subunits to form inhibin A (αβA) or inhibin B (αβB). Activin is composed of three combinations of the β subunits: activin A (βAβA), activin AB (βAβB) and activin B (βBβB). Activin is a member of the transforming growth factor β (TGF-β) superfamily of growth and differentiation factors that include TGF-β, Müllerian-inhibiting substance (MIS) and bone morphogenic proteins. Follistatin is structurally unrelated to either inhibin or activin. It is a highly glycosylated pituitary peptide that inhibits gonadotrope function but at one-third the potency of inhibin. All three of these peptides have their major influence on the expression of the FSH-β gene. Of these peptides, inhibin appears to be the most biologically important regulator of the FSH gene, directly suppressing its activity. The other two peptides appear to act within the pituitary cells through locally released second messengers or autocrine peptides. Activin B stimulates FSH release. Activins also affect the gonads directly by increasing the activity of the aromatase enzyme in the ovary and stimulating proliferation of spermatogonia in the testes.

Mechanism of action of gonadotropins

There are distinct FSH and LH receptors. The latter also bind the closely related hCG molecule. Receptors for both glycoprotein hormones FSH and LH are located in the plasma membranes of the granulosa cells in the ovary and the Sertoli cells in the testes. Ovarian thecal cells and testicular Leydig cells only display LH receptors. In addition to regulating steroidogenesis and gametogenesis, gonadotropins regulate expression of their own receptors in a dose-dependent fashion. FSH also induces LH/hCG receptor formation in granulosa and Sertoli cells.

Although gonadotropin receptors are normally present in very low concentrations on the cell surface, they have high specificity and affinity for their ligands. The interactions between the glycoprotein dimer and its receptor lead to conformational changes in the receptor. This then activates a membrane-associated G protein-coupled signaling system. Although the G protein-coupled cAMP pathway is the principal mediator of both FSH and LH receptor activity, activation of the protein kinase C system can also occur.

In addition to activating specific intracellular signaling processes, binding of the gonadotropin to its receptor also initiates a regulatory function termed desensitization. Desensitization reduces the cell's responsiveness to ongoing stimulation. In the first phase of desensitization, the gonadotropin receptor becomes “uncoupled” from its downstream activity so that it no longer activates adenylate cyclase. In the second, slower phase of desensitization, the degradation rate for the receptors is increased. This latter process is called “downregulation.” Both are involved in the activities of GnRH agonists and antagonists.

2

Steroid hormone biosynthesis

Cholesterol and the steroid production pathway

Cholesterol is the building block of steroid hormones. All steroid-producing organs with the exception of the placenta can synthesize cholesterol from acetate. Under most circumstances, however, local synthesis cannot meet demand and circulating cholesterol must be used. The major carriers of cholesterol in the bloodstream are the low-density lipoproteins (LDLs). LDL is removed from the blood by steroidogenic cells using cell surface receptors that recognize specific surface proteins on LDL called apoproteins. Once in the cell, cholesterol is carried through a sequence of enzymatic changes to produce a final product that belongs to one of the major classes of steroid hormones: progestins, androgens and estrogens (sex), glucocorticoids (sugar) and mineralocorticoids (salt). All steroid-producing tissues use a common sequence of precursor molecules and enzymes (Fig. 2.1). Tissue specificity is conferred by the presence or absence of specific enzymes in the sequence. For instance, the gonads differ from the adrenal glands in that ovaries and testes do not express the 21-hydroxylase or 11β-hydroxylase enzymes that are necessary to produce corticosteroids. Therefore, the gonads only produce three classes of steroids: progestins, androgens and estrogens.

During conversion of cholesterol to steroid metabolites, the number of total carbon atoms decreases sequentially. Progestins have 21 carbons (C-21); androgens have 19 carbons (C-19); and estrogens have 18 carbons (C-18). Thus, progestins are obligatory precursors of both androgens and estrogens. Likewise, androgens are obligatory precursors of estrogens.

Most of the steroidogenic enzymes are members of the cytochrome P450 class of oxidases. A single mitochondrial protein P450scc, the cholesterol side chain cleavage enzyme, mediates all steps in the conversion of cholesterol to pregnenolone. The activity of this protein represents the rate-limiting step for the entire steroid pathway. Not surprisingly, it is also the major site of tropic hormone stimulation. Genetic mutations of P450scc are very rare and usually lethal. No steroid hormones can be produced by an individual with an inactive P450scc enzyme.

Once pregnenolone is formed, steroid production can proceed down one of two paths, through either progesterone or 17α-hydroxypregnenolone. All but two of the enzymes responsible for producing the steroid hormones are packaged within the endoplasmic reticulum, together with other members of the P450 system. The biosynthetic units are very tightly linked together, thereby ensuring that very few of the steroid intermediates leave the cell. This packaging is also highly efficient in that it can convert an entire class of steroids to another. Thus, 17,20-desmolase will convert all progestins to androgens, and aromatase will convert all androgens but dihydrotestosterone (DHT) to estrogens.

Sites of production

Ovary

In the ovary, steroid production occurs in a two-cell system (Fig. 2.2). Theca cells produce androgens. These androgens diffuse into the granulosa cells where they are converted to estrogens. Tropic hormones regulate specific steps in the sex steroid cascade. Theca cells respond to luteinizing hormone (LH) by increasing the number of LDL receptors and hence cholesterol entry into the cells. LH also stimulates P450scc activity, allowing increased androgen production. When these androgens diffuse into granulosa cells, they are metabolized by aromatase into estrogens. Follicle-stimulating hormone (FSH) induces the activity of aromatase in the granulosa cell, thereby increasing the conversion of androgens to estrogens. The single aromatase gene has many promoter sites. These are responsive to cytokines, cyclic nucleotides, gonadotropins, glucocorticoids and growth factors.

Testes

In the testes, androgen production occurs largely in the Leydig cells under the influence of LH. Androgens produced in the Leydig cells either enter the bloodstream directly or diffuse into nearby Sertoli cells. Sertoli cells can convert androgens to estrogens using aromatase or reduce them to dihydrotestosterone via 5α-reductase. Because the specific cell types within the differentiated male and female gonads have common embryonic origins (Chapter 5), the mechanisms for steroid production in the testes very much parallel those in the ovary.

Adrenals

Sex hormone production by the adrenals occurs largely as a by-product of corticosteroid biosynthesis. The contribution of adrenal sex steroids to the total pool of circulating sex steroids is typically small, although there are several important exceptions. The ovaries of postmenopausal women no longer produce significant amounts of steroid hormones so adrenal androgen production can become clinically significant. In pregnancy, the placenta cannot synthesize cholesterol from acetate. Rather, it relies on adrenal androgens of both maternal and fetal origin to make estrogens.

With the exception of P450scc, inherited defects in any of the enzymes involved in steroidogenesis are associated with clinical syndromes resulting either from accumulation of a precursor product or absence of a key end-product. For example, an inherited deficiency of the enzyme 21-hydroxylase in the adrenal gland will lead to a deficiency in adrenal cortisol production. Low cortisol levels feed back to promote enhanced production of adrenal glucocorticoids. The enzymatic block, however, results in an accumulation of precursor progestins, some of which will be shunted down functional androgen biosynthetic pathways. If the 21-hydroxylase deficiency occurs in a female fetus, the increase in androgen production may cause masculinization of the external genitalia, known as congenital adrenal hyperplasia syndrome (Chapter 27). Similarly, disorders of male sexual differentiation and development may result from genetic defects in androgen production (Chapter 26).

3

Steroid hormone mechanism of action and metabolism

Mechanisms of steroid action

Steroid hormones exert their effects via a unifying basic mechanism: the induction of new protein synthesis in their target cells. These induced proteins may be hormones themselves or other molecules important to cell function, such as enzymes. It is the newly synthesized proteins that are ultimately responsible for steroid hormone activity (Fig. 3.1).

Once a steroid hormone is secreted by its endocrine gland of origin, 95–98% of it circulates in the bloodstream bound to a specific transport protein. The remaining 2–5% is free to diffuse into all cells. Once inside the cell, a steroid can only produce responses in cells that have specific intracellular receptors for that hormone. Specific receptor binding is key to the action of steroids in their target tissues. Thus, estrogen receptors are found in the brain and in target cells specific to female reproduction, such as the uterus and breast. Facial hair follicles and penile erectile tissue contain androgen receptors. Glucocorticoid receptors are found in all cells because glucocorticoids are necessary to regulate global functions like metabolism and stress.

All members of the major classes of sex steroids (e.g., androgens, estrogens and progestins) act through a similar sequence of events to exert cellular responses: (i) transfer of the steroid into the nucleus; (ii) intranuclear receptor binding; (iii) alterations in receptor conformation that convert the receptor from an inactive to an active form; (iv) binding of the steroid–receptor complex to regulatory elements on deoxyribonucleic acid (DNA); (v) transcription and synthesis of new messenger ribonucleic acid (mRNA); and (vi) translation of mRNA with new protein synthesis in the cell. The mechanisms of action of glucocorticoids and mineralocorticoids differ from those of the sex steroids. Glucocorticoids and mineralocorticoids bind to their receptors in the cell cytoplasm. Hormone–receptor complexes are subsequently transported to the nucleus where they bind to the DNA.

There are three important structural domains in each steroid hormone receptor that correspond to the molecule's three functions: (i) steroid hormone binding; (ii) DNA binding; and (iii) promotion of gene transcription. It is therefore not surprising that all steroid hormone receptors have remarkable structural similarities at the copy DNA (cDNA) level. The receptors for thyroid hormone, vitamin D and vitamin A also have similar DNA binding domains. Together with the sex hormone receptors, these receptors form a “superfamily” of nuclear receptors in which the thyroid hormone and vitamin A and D receptors are thought to be the most evolutionarily primitive. The latter three receptors are highly conserved, likely a result of their importance in early embryonic development. Glucocorticoid and progesterone receptors arose more recently in evolution. Their actions are less global, regulating acute metabolic changes in highly differentiated cells.

Expression of genes regulated by steroid hormones is controlled by four specific elements: (i) promoters; (ii) steroid-responsive enhancers; (iii) silencers; and (iv) hormone-independent enhancers. Steroid-responsive enhancers are DNA binding sites for activated steroid–receptor complexes and are known as steroid response elements (SREs). SREs are a very important component of hormone-responsive genes; they determine steroid specificity.

Agonists and antagonists

Steroid hormone potency depends on a combination of the affinity of the receptor for the hormone or drug, the affinity of the hormone–receptor complex for the SRE, and the efficiency of the activated hormone–receptor complex in regulating gene transcription. Molecules with high affinities for a receptor and whose subsequent hormone–receptor complex has high affinity for an SRE lead to prolonged occupancy of the SRE and sustained gene transcription. Such molecules act as agonists for the parent compound. Other molecules may have a high affinity for a receptor, but the hormone–receptor complex binds inefficiently to the SRE. Still others occupy the steroid receptor in a way that allows them to bind to the SRE but prevents RNA polymerase from coupling with factors necessary for gene transcription. The latter act as antagonists to the parent compound. An example of a compound with mixed agonist/antagonist properties is the drug tamoxifen. Tamoxifen is an antiestrogen that acts as a potent antagonist to the estrogen receptor in breast tissue and as an agonist in uterus and bone. Such tissue-specific effects are dependent upon specific silencers and hormone-independent enhancers present in each tissue. Another widely used agonist/antagonist is the non-steroidal compound clomiphene citrate. Clomiphene can be used to induce ovulation, although its actions are complex. Clomiphene's interactions with estrogen receptors in the pituitary gland and hypothalamus result in binding of receptors, but without subsequent efficient stimulation of estrogen-associated gene transcription. The hypothalamus senses this as a hypo-estrogenic state and gonadotropin-releasing hormone (GnRH) pulse frequency increases. Pituitary follicle-stimulating hormone (FSH) production is stimulated and increased FSH release drives ovarian production of estrogen. When clomiphene is stopped, the hypothalamic estrogen receptors are again available for estrogen binding and appropriate SRE responses. The hypothalamus is able to respond normally to the high concentrations of circulating estrogen from the ovaries and an ovulatory luteinizing hormone (LH) surge occurs (Chapter 14).

Steroids in the circulation

Steroid hormones are transported in the bloodstream bound to specific proteins. Protein-bound hormone does not traverse the plasma membrane of the cell. Nearly 70% of circulating testosterone and estradiol is bound to a β globulin known as sex hormone-binding globulin (SHBG). Another 30% is loosely bound to albumin, leaving only 1–2% unbound and capable of entering cells. SHBG binds all other estrogens and androgens to varying degrees; less than 10% of any steroid is free in the bloodstream. Pregnancy, estrogen and hyperthyroidism all increase SHBG synthesis. Androgens, progestins, corticoids and growth hormone all decrease SHBG. Weight gain can also decrease SHBG through an insulin-mediated effect on its synthesis. In keeping with the law of mass action, changes in the concentration of SHBG will affect the amount of free, unbound circulating steroid. Changes in SHBG will therefore affect the biologic action of steroids by altering the amount available to cells.

Unlike the other sex steroids, progesterone is carried in the blood by a glycoprotein, corticosteroid-binding globulin (CBG). CBG is also known as transcortin. As suggested by its name, it binds and carries glucocorticoids.

Steroid metabolism

With the exception of the progestins, androgens are obligatory precursors of all other steroid hormones. Therefore, androgens are made in all steroid-producing tissues including the testis, ovary and adrenal gland. The major circulating androgen in men is testosterone which is produced by the testes. Testosterone is the most potent androgen. Its hormonal action is produced either directly through binding to the androgen receptor or indirectly after conversion to dihydrotestosterone (DHT) within the target tissue. Testosterone acts directly on the internal genital tract in male fetuses during sexual differentiation (Chapter 6) and on skeletal muscle to promote growth. DHT acts on the genital tracts of male fetuses to stimulate differentiation of the external genitalia. In adult men, DHT acts locally to maintain masculinized external genitalia and secondary sexual characteristics such as facial and pubic hair. Other major circulating androgens in men include androstenedione, androstenediol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S).

All of the above androgens, including testosterone and DHT, can be found in the circulation of women. With the exception of androstenedione, the concentrations of the androgens are considerably lower in women than in men. Androstenedione is unique in that only about 4% of it is bound to SHBG in the circulation in women. The remainder is bound more loosely to albumin. Circulating androstenedione functions largely as a prohormone and is converted within target tissues to testosterone, estrone and estradiol.

Estradiol (E2) is the major estrogen secreted by the ovary. Estrone (E1) is also secreted by the ovary in significant amounts. Estriol (E3), by contrast, is not produced in the ovary at all. Estriol is produced from estradiol and estrone in peripheral tissues and from androgen in the placenta; it is considered a less active “metabolite” of the more potent estrogens. Direct conversion of androgens into estrone can occur in skin and adipose tissue. This has important clinical implications in the obese female. In all women, the daily production of the prohormone androstenedione is 10 times higher than that of estradiol. In obese women, conversion of androgens to estrone in adipose tissue can become a major source of excessive amounts of circulating estrogen.

The adrenal gland is an important source of sex steroids in both men and women. Androstenedione, DHEA and DHEA-S are the major circulating androgens of adrenal origin and adrenal androgen production follows a circadian rhythm that parallels cortisol secretion. Adrenal androgens assume an important role in the postmenopausal woman. In the absence of ovarian estrogen production, adrenal androgens act as a major source for estrogen precursors.

The most abundant progestin in the circulation is progesterone. The ovary, testis, placenta and adrenal gland can all produce progesterone. 17-Hydroxyprogesterone of adrenal and ovarian origin represents the other major circulating progestin. Both progestins are largely bound by transcortin.

Steroid excretion

Steroids are excreted in urine and bile. Prior to elimination, most active steroids are conjugated as either sulfates or glucuronides. Some sulfated conjugates such as DHEA-S are actively secreted. These conjugated hormones can serve as precursors to active hormone metabolites in target tissues that have the enzymes to hydrolyze the ester bonds involved in the conjugation.

4

Reproductive genetics

Chromosomes

Human chromosomes are complex structures consisting of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and protein. Each single helix of DNA is bound at each end with a telomere and has a centromere somewhere along the length of the chromosome. The telomere protects the ends of the chromosome during DNA replication. Telomere shortening is associated with aging. The centromere is the site at which the mitotic spindle will attach and is necessary for proper segregation of chromosomes during cell division. The centromere divides the chromosome into two arms, identified as p (petit) for the short arm and q for the long arm. The centromere can be positioned anywhere along the arm of the chromosome and its location has been used to group like chromosomes together as central (metacentric), distal (acrocentric) or others (submetacentric). The length of the chromosome plus the position of its centromere are used to identify individual chromosomes within the 22 pairs of autosomes and one pair of sex chromosomes. Chromosomes are numbered in descending order of size; 1 is the largest. The only exception to this rule is chromosomes 21 and 22; 22 is larger than 21. Because of the historical convention of associating Down syndrome with trisomy 21, this chromosome pair was not renamed when the size difference became apparent.

A karyotype is a display of chromosomes ordered from 1 to 22 plus the sex chromosomes, with each chromosome oriented so that the p arm is on top. Females have a 46XX karyotype and males a 46XY karyotype (Fig. 4.1a and b).

Mitosis and meiosis

These are two distinct types of cell divisions, with several common features. The first is the need to duplicate the entire chromosome content of the cell prior to division. Both also use the cell machinery of the parent cell to make the DNA, RNA and new proteins that will participate in the cell division. Finally, both processes rely on using the mitotic spindle to separate the chromosomes into the two poles of the cell that are destined to become the progeny of that cell. Mitosis and meiosis differ in that duplicated chromosomes behave differently after DNA replication (Fig. 4.2). In mitosis, there is no difference in total chromosome content between parent and daughter cells; in meiosis, the chromosome number of the daughter cells is eventually reduced from 46 to 23, which is necessary to convert the diploid germ cell precursors originating in the embryo into haploid (1n) germ cells. These haploid germ cells will produce a new diploid organism at fertilization. Meiosis promotes exchange of genetic material through chromatid crossing over; mitosis does not.

During the interphase preceding cell division, the DNA for each chromosome is duplicated to 4n. Thus, each chromosome consists of two identical chromatids joined at the centromere.

In mitosis, the chromosomes first shorten and thicken and the nucleoli and nuclear membrane break down (prophase). During metaphase, a mitotic spindle forms between the two centrioles of the cell and all chromosomes line up on its equator. The centromere of each chromosome splits and one chromatid from each chromosome migrates to the polar ends of the mitotic spindle (