Progestogens in Obstetrics and Gynecology

Foreword
Preface to the Second Edition
Contents
Chapter 1: Physiology of Progesterone
	1 Introduction
	2 The Mechanisms of the Cellular Action of Progesterone
		2.1 Genomic Actions of Progesterone and the Cytosolic Progesterone Receptor
		2.2 The Role of Co-Regulators in Progesterone Signaling
		2.3 Non-genomic Actions of Progesterone
	3 The Physiologic Effects of Progesterone
		3.1 The Effect of Progesterone on the Immune System
		3.2 The Role of Progesterone in Non-pregnant Women
			3.2.1 Progesterone and the Menstrual Cycle
			3.2.2 Progesterone and the Myometrium in the Non-pregnant Uterus
			3.2.3 The Effect of Progesterone on the Uterine Cervix during the Menstrual Cycle
		3.3 Progesterone and Pregnancy
			3.3.1 The Role of Progesterone in the Maintenance of Normal Pregnancy and Parturition
			3.3.2 The Nuclear Progesterone Receptor in the Myometrium during Pregnancy and Parturition
			3.3.3 The Membrane Progesterone Receptor during Pregnancy and Parturition
			3.3.4 Progesterone Oxytocin Responsiveness and Ca2+ Fluxes
			3.3.5 The Interplay Between NFκB and Progesterone in Pregnancy Maintenance and in the Onset of Labor
			3.3.6 Changes in Myometrial Progesterone Co-Regulators during Pregnancy
			3.3.7 Progesterone Receptor in Fetal Membranes, Decidua, Placenta
			3.3.8 The Effect of Progesterone on the Cervix During Pregnancy
				3.3.8.1 Collagen Remodeling
				3.3.8.2 Changes in Glycosaminoglycans
				3.3.8.3 Suppression of Metalloproteinases
				3.3.8.4 Modulation of the Inflammatory Response in the Uterine Cervix
	4 Conclusions
	References
Chapter 2: Pharmacology of Progestogens
	1 Introduction
	2 Classification of Progestogens
	3 Pharmacokinetics and Pharmacology of Progestogens
	4 Thrombotic Risk of Progestogens
	5 Conclusions
	References
Chapter 3: Progestogens in Infertility Practice
	1 Introduction
	2 Role of Progesterone in Endometrial Ripening
	3 Role of Progesterone in Implantation
		3.1 Cytokines Acting in Implantation
		3.2 Action of Progesterone on Cytokines
	4 Luteal Phase Insufficiency
		4.1 Formation of the Corpus Luteum (CL)
		4.2 Evaluation of the Luteal Phase
		4.3 Luteal Insufficiency in Stimulated Cycles
			4.3.1 Non ART Cycles
			4.3.2 ART Cycles
	5 Types of Hormone Supplementation in Infertility
		5.1 Human Chorionic Gonadotropin (hCG)
		5.2 Micronized Progesterone
		5.3 Intramuscular Progesterone
		5.4 Estradiol Plus Progesterone
		5.5 Progesterone with Gonadotrophin-Releasing Hormone
		5.6 Synthetic Progestogens
	6 Conclusions
	References
Chapter 4: Progestogens in Threatened Miscarriage
	1 Introduction
	2 Natural History
	3 Diagnosis of Luteal Deficiency
		3.1 Progesterone Levels
		3.2 Other Markers of Luteal Phase Insufficiency
		3.3 Cause of Luteal Phase Insufficiency
	4 Confounding Factors
	5 Effect of Progestogen Supplementation
	6 Subgroups of Threatened Miscarriage
		6.1 Subchorionic Hematoma
		6.2 Threatened Miscarriage After Recurrent Miscarriage
	7 Safety and Side Effects
	8 Conclusions
	References
Chapter 5: Progestogens and Recurrent Miscarriage
	1 Introduction
	2 The Role of Progesterone
		2.1 Potential Mechanisms of Action of Progestogens in Preventing RM
			2.1.1 Disturbed Metabolism of Cholesterol and Progesterone in Recurrent Miscarriages
		2.2 Effects of Progesterone on the Uterus and the Endometrial Environment
			2.2.1 Endometrial Development and Luteal Phase Deficiency
			2.2.2 Induction of Uterine Quiescence
		2.3 Immunological Role of Progestogens
			2.3.1 Involvement of Progesterone in Maternal Cytokine Production
			2.3.2 Involvement of Progesterone in Maternal Natural Killer (NK) Cells
			2.3.3 Involvement of Progesterone in Anti-trophoblast Antibodies
	3 The Evidence for Progesterone Use in Recurrent Miscarriage
	4 Safety of Progestogens for Prevention of Recurrent Miscarriage
		4.1 Safety of the Mother
		4.2 Safety of the Fetus
	5 Future Research
	6 Conclusions
	References
Chapter 6: Progestogens in Preterm Labour Prevention: An Update
	1 Introduction
	2 Role of Progesterone in Obstetrics
	3 Routes of Administration: Key Differences
		3.1 Oral Administration
		3.2 Intramuscular Administration
		3.3 Vaginal Administration
		3.4 Rectal Administration
	4 Progesterone and PTB: “Which, When and How”
	5 Progesterone and Twin-Pregnancy
	6 Progesterone as a Tocolytic Agent and/or for Maintenance Therapy?
	7 Future Strategies on PTB Prevention
	8 Conclusions
	References
Chapter 7: Abnormal Uterine Bleeding
	1 Introduction
	2 Physiology of Menstruation
		2.1 Pathophysiology of Anovulatory Bleeding
	3 Diagnosis of AUB
		3.1 Imaging
			3.1.1 Ultrasound
			3.1.2 Hydrosonography
			3.1.3 Magnetic Resonance Imaging (MRI)
			3.1.4 Hysteroscopy
	4 Biopsy
	5 Bleeding Dyscrasias
	6 Principles of Treatment
		6.1 Acute Uterine Bleeding
			6.1.1 High Dose Intravenous Estrogen
			6.1.2 Hemodynamically Stable Patients
		6.2 Abnormal Uterine Bleeding in Adolescents
		6.3 Perimenopausal Bleeding
		6.4 Chronic Abnormal Bleeding
	7 LNG-IUS
	8 Endometrial Hyperplasia
	9 Other Forms of Treatment
		9.1 Receptor Modulators
		9.2 NSAIDS
		9.3 Antifibrinolytic Drugs
	References
Chapter 8: Progestogens in Contraception
	1 Development and Classification of Protestogens in Contraception
		1.1 The Time of Introduction into the Market
		1.2 Classification According to Molecular Structure
			1.2.1 Derivatives of Testosterone
			1.2.2 Derivatives of Progesterone
			1.2.3 Derivatives of Spironolactone
		1.3 Classificiation According to Interaction with Steroid Receptors
	2 Progestogens in Combined Hormonal Contraceptives
		2.1 Health Risks of Combined Hormonal Contraceptives in Relation to the Different Progestogens
	3 Progestogen Only Contraception
		3.1 Common Features of Progestogen Only Contraception
			3.1.1 General Principle of Action
			3.1.2 Very Low or Absence of Cardiovascular Risks [26, 27]
			3.1.3 Contraindications for Progesterone Only Contraception
			3.1.4 Side Effects
			3.1.5 Additional Benefits and Therapeutic Indications
			3.1.6 High Efficacy in Typical Use
		3.2 Oral Preparations [28]
			3.2.1 Health Risks
				3.2.1.1 Bone Health
			3.2.2 Side Effects
			3.2.3 Special Benefits
			3.2.4 Contraindications
		3.3 Progestogen Implants [30, 31]
			3.3.1 The Etonogestrel Releasing Hormonal Implant Implanon®
				3.3.1.1 Efficacy
				3.3.1.2 Health Risks
				3.3.1.3 Side Effects
				3.3.1.4 Additional Benefits
				3.3.1.5 Contraindications
		3.4 Injections (Intramuscular and Subcutaneous) [32]
			3.4.1 Efficacy
			3.4.2 Health Risks
			3.4.3 Side Effects
			3.4.4 Benefits
			3.4.5 Contraindications
		3.5 Levonorgestrel Containing Intrauterine Systems [34]
			3.5.1 Efficacy
			3.5.2 Health Risks
			3.5.3 Side Effects
			3.5.4 Additional Benefits
			3.5.5 Contraindications
	References
Chapter 9: Progestogens and Endometriosis
	1 Introduction
	2 Mechanisms of Progesterone Resistance in Endometriosis
		2.1 Environmental Toxicants in Progesterone Resistance
		2.2 Retinoid Resistance
	3 Inflammatory Reaction Around Endometriotic Deposits
		3.1 Effect of Sex Hormones on Inflammatory Reaction
	4 Genetic Basis of Endometriosis
		4.1 Epigenomics and Epigenetics
	5 Evasion of Immune Clearance
	6 Comorbity of Endometriosis
	7 Progesterone Actions in the Female Brain
	8 Progestogens as Treatment
		8.1 Mode of Action
		8.2 Different Progestogens
			8.2.1 Dydrogesterone
			8.2.2 Dienogest
			8.2.3 Medroxy Progesterone Acetate (MPA)
			8.2.4 Cyproterone Acetate
			8.2.5 Levonorgestrel Intrauterine System (LNG-IUS)
			8.2.6 Norethindrone Acetate (NETA)
			8.2.7 Effect of Progestogens on Endometriosis Related Infertility
		8.3 Oral Contraceptive Pill (OCP)
		8.4 Anti-Progestogens (Gestrinone)
		8.5 Choice of Treatment
	9 Other Modes of Treatment
		9.1 AKR1C3
	10 Conclusions
	References
Chapter 10: Progestogens and Breast Cancer
	1 Introduction
	2 Progesterone Receptors
	3 Breast Cancer -the Progesterone Effect
	4 Local Production and Action of Progestogens
	5 Progesterone and Migration of Breast Cancer Cells
	6 Protease Activated Receptors and Progesterone
	7 RANK/RANKL and Progesterone
	8 Progesterone and E-Cadherin
	9 Bazedoxifene
	10 Conclusion
	References
Chapter 11: Progestogens in Endometrial Cancer
	1 Introduction
	2 Progesterone for Fertility Preservation
		2.1 Are There Any Risks?
		2.2 Workup Prior to Treatment
			2.2.1 Tissue Biopsy
			2.2.2 Imaging
			2.2.3 Additional Invasive Procedures
			2.2.4 Genetic Counseling
		2.3 Prognostic Factors
		2.4 Types of Progesterone
		2.5 Outcome
			2.5.1 Repeat Treatment for Recurrence After Complete Response?
			2.5.2 Outcome for Progestin Releasing Intrauterine Devices
			2.5.3 Combined Progestins Treatment and Hysteroscopy
		2.6 Follow Up
	3 Progesterone in Advanced Endometrial Cancer
	4 Novel Approaches
		4.1 Fourth-Generation Progestins
		4.2 Progesterone Receptor Expression and Reversal of Progesterone Resistance
	5 Conclusions
	References
Chapter 12: Progestogens and the Menopause
	1 Introduction
	2 Progestogens and Osteoporosis
	3 Progesterone, Hot Flushes and Night Sweats
	4 Progesterone and Venous Thromboembolism
	5 Progesterone and the Brain
		5.1 Progesterone in Alzheimer’s Disease
		5.2 Traumatic Brain Injury (TBI)
	6 Cardiovascular
	7 Conclusions
	References
Chapter 13: Progestogens and Autoimmunity
	1 Sexual Dimorphism in Autoimmunity
	2 The Mechanism Mediating the Immunomodulatory Effects of Progestogens
		2.1 Progestogen Signaling
		2.2 Innate and Adaptive Immunity
			2.2.1 The Innate Immune System
			2.2.2 The Adaptive Immune System
	3 Progestogens Effect on Specific Autoimmune Diseases
		3.1 Rh Rheumatoid Arthritis (RA)
		3.2 Multiple Sclerosis (MS)
		3.3 Systemic Lupus Erythematous (SLE)
		3.4 Autoimmune Thyroid Disease (AITD)
	4 Immunomodulation and Prevention of Preterm Birth
	5 Progestogen Hypersensitivity
	References
Chapter 14: Progestogens in Non Gynecological Indications
	1 Introduction
	2 Progesterone in Evolution
	3 Progesterone in Males
		3.1 Progesterone Receptors
		3.2 Effects of Progesterone in the Male
		3.3 Progesterone and Prostate Cancer
			3.3.1 Anti-Androgenic Effect
			3.3.2 Anti-Gonadotrophic Effect
			3.3.3 Cytotoxic Effect
	4 Progesterone, the Neurotrophic Hormone
		4.1 Multiple Sclerosis (MS)
		4.2 Brain Trauma and Stroke
		4.3 Peripheral Neuropathy
		4.4 Epilepsy
		4.5 Parkinson’s Disease
		4.6 Progesterone and Spinal Cord from Neurodegeneration.
		4.7 Progesterone in ADD, and ADHD
		4.8 Anxiety
	5 Other Therapeutic Effects of Progesterone
		5.1 Progesterone and Statin Use
		5.2 Asthma
		5.3 Arthritis
		5.4 Carpal Tunnel Syndrome
	6 Conclusions
	References