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Presynaptic receptors SSRI Figure 18.1 Schematic diagram of 5-HT metabolism. N H Tryptophan Presynaptic neuron 1A TPH MAO Tryptophan 5-HT 5HIAA 1B Synapse 1A Postsynaptic neuron 2A 2C Serotonin transporter (5-HTT) Postsynaptic receptors GENETICS 163 NH 2 NH 2 NH 2 O N H OH OH HO HO Tryptophan hydroxylase N H O Aromatic amino acid decarboxylase NH 2 HO HO 5-Hydroxytryptamine Monoamine oxidase A 5-Hydroxytryptophan Figure 18.2 Serotonin (5-HT) synthesis and catabolism. N H B 6 O 5-Hydroxyindoleacetic acid OH N H 5-Hydroxytryptamine
164 THE PREMENSTRUAL SYNDROMES the serotonin or other neurotransmitter pathways may influence susceptibility, with cyclical ovarian hormone fluctuations providing the environmental trigger. Allelic variants can occur anywhere in the genome: some are found within exons, which are the coding regions of genes, whereas others are located in introns, promoter regions, or sites that are not closely linked to any known expressed gene. 62 Types of genetic polymorphisms Single-nucleotide polymorphisms (SNPs) are allelic variants that have been generated as the result of conversion of one nucleotide to another at a homologous position. When present within a coding region (exon) of a gene, the expressed product may or may not have a single amino acid difference, depending on the resulting codon change. In some cases, the resulting codon stops the transcription process and results in the production of a truncated peptide. SNPs that are located in regulatory regions of an expressed gene can alter the transcription efficiency of that gene but not the protein sequence. 62 Some polymorphisms coincide with the target nucleotide sequences recognized by restriction enzymes. Polymorphisms that occur at restriction enzyme sites are known as restriction fragment length polymorphisms (RFLPs). RFLPs are extremely useful because they can be used to identify genetic markers. 63 Deletion or insertion mutants have also been found in functional genes. The consequence of a deletion depends on its precise location: whether it produces a mutation that results in an alteration in the reading frame of the gene and the function of the expressed product. Other types of allelic variance in association with a particular gene are repetitive sequence elements which are arranged in tandem. Depending on the repeat unit length and the degree of repetition per locus, these repetitive sequence elements are known as satellite, minisatellite and microsatellite. Polymorphisms created by such elements are termed variable number of tandem repeats (VNTR) polymorphisms. 63 Below, we describe potential candidate gene polymorphisms suitable for study in PMDD, and include relevant evidence from numerous psychiatric studies. Candidate genes in the serotonergic pathway Tryptophan hydroxylase TPH catalyzes the rate-limiting step in serotonin synthesis, and is one of the most important regulators of the serotonergic system. In humans, two different TPH genes exist, which encode two enzymes (TPH1 and TPH2), with an overall sequence homology of 71%. 64 TPH1 is expressed in peripheral tissues and in the pineal body, whereas TPH2 appears to be responsible for serotonin synthesis in the rest of the brain. Since the existence of TPH2 is a relatively recent discovery (2003), most studies conducted to date have focused on TPH1 markers. Numerous TPH1 sequence variants have been reported. 65 Of these, the most commonly studied are the two promoter polymorphisms G-6526A and G-5806T, and the two markers A218C and A779C in intron 7. It has been suggested that sequence variations within the promoter region may modify TPH1 expression and affect serotonin synthesis, and this has been supported by successive deletion analysis of the promoter region, which led to a decrease in promoter activity. 66 The A218C marker has been studied extensively in psychiatric disorders. 67 The exact mechanism linking the A218C polymorphism to reduced expression of the gene product remains unknown; however, the functional relevance of this polymorphism has been demonstrated for a series of clinical syndromes (e.g. bipolar disorder, suicide attempts, and suicidal behavior). 68–74 The A allele has been associated with decreased serotonin synthesis 75 and slower response to SSRIs 76,77 in subjects with major depressive disorders. Numerous studies have attempted to link TPH1 polymorphisms with a variety of mood disorders, but have given conflicting data. 78–81 In a recent study, we found no significant associations between PMDD and the G-6526A, G-5806T, or the A218C polymorphisms of the TPH1 gene. 82 Until recently, TPH1 was believed to be the sole rate-limiting enzyme for neuronal serotonin synthesis, which occurs in the raphe nuclei of the brainstem. This lack of association is not surprising in the light of the discovery of a second tryptophan hydroxylase (TPH2) isoform, 64 which is expressed predominantly in the brainstem but not in peripheral tissues. 83,84 Initial reports of TPH2 polymorphisms indicate an association between several SNPs and major depression. 85–87 Thus, TPH2 may be a strong candidate gene for future study in PMDD. The serotonin transporter The serotonin transporter (5-HTT) protein is the primary mechanism for removing serotonin from the synaptic cleft. Three common 5-HTT polymorphisms have been studied in psychiatric disorders: 5-HTT LPR, VNTR-2, and 3�UTR G/T. The 5-HTT LPR is a 44 nucleotide insertion/deletion in the promoter region giving rise to long (L) or short (S) alleles. 88 This polymorphism has been evaluated in several studies. Infants with the short homozygous (S/S) 5-HTT LPR genotype had higher scores on negative emotionality and distress
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The Premenstrual Syndromes
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© 2007 Informa UK Ltd First publis
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vi CONTENTS 10. Pathophysiology I:
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viii LIST OF CONTRIBUTORS Uriel Hal
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Preface Somatic, affective, and beh
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1 History of the premenstrual disor
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and estrogen/progesterone imbalance
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Dalton’s PMS, new, more precise t
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Many other therapeutic areas have b
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2 The diagnosis of PMS/PMDD - the c
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section of gynecological disorders,
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Universal acceptance of a diagnosti
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Extremely severe Severe None Severi
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Table 2.5 Differential diagnosis of
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17. Halbreich U, Borenstein J, Pear
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22 THE PREMENSTRUAL SYNDROMES pharm
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24 THE PREMENSTRUAL SYNDROMES IS PM
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26 THE PREMENSTRUAL SYNDROMES 18. S
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28 THE PREMENSTRUAL SYNDROMES METHO
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30 THE PREMENSTRUAL SYNDROMES Table
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32 THE PREMENSTRUAL SYNDROMES DAILY
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34 THE PREMENSTRUAL SYNDROMES Table
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36 THE PREMENSTRUAL SYNDROMES to ot
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38 THE PREMENSTRUAL SYNDROMES prosp
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40 THE PREMENSTRUAL SYNDROMES exami
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42 THE PREMENSTRUAL SYNDROMES healt
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44 THE PREMENSTRUAL SYNDROMES deter
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46 THE PREMENSTRUAL SYNDROMES 35. B
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6 Comorbidity of premenstrual syndr
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inhibitor, medications routinely us
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symptoms as well as worsening of co
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7 The clinical presentation and cou
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ecause ovulation is less frequent a
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to try self-help strategies that ar
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40. WHO. International Classificati
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64 THE PREMENSTRUAL SYNDROMES ∆ 4
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66 THE PREMENSTRUAL SYNDROMES Anter
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68 THE PREMENSTRUAL SYNDROMES REFER
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70 THE PREMENSTRUAL SYNDROMES store
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72 THE PREMENSTRUAL SYNDROMES contr
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74 THE PREMENSTRUAL SYNDROMES Serot
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76 THE PREMENSTRUAL SYNDROMES These
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78 THE PREMENSTRUAL SYNDROMES level
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80 THE PREMENSTRUAL SYNDROMES 110.
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10 Pathophysiology I: role of ovari
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different neuromodulatory profile f
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studied, reflecting in part interes
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disturbed in these patients. Compar
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mid-luteal phases of the menstrual
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hyposensitivity or altered circadia
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52. Osterlund MK, Halldin C, Hurd Y
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135. Facchinetti F, Genazzani AD, M
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11 Pathophysiology II: neuroimaging
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orbitofrontal cortex (OFC), and ant
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EVIDENCE OF ALTERED GABAERGIC FUNCT
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the preclinical data indicating tha
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19. Nordstrom AL, Olsson H, Halldin
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110 THE PREMENSTRUAL SYNDROMES ster
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Page 144 and 145: 15 Psychotropic therapies Meir Stei
Page 146 and 147: Table 15.2 Intermittent dosing (lut
Page 148 and 149: Table 15.3 Intermittent vs continuo
Page 150 and 151: clinical evidence that concomitant
Page 152: 46. Yamada K, Kanba S. Effectivenes
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Page 162 and 163: 17 Clinical evaluation and manageme
Page 164 and 165: prior to menses) compared with the
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Page 168 and 169: premenstrual cognitive disturbance,
Page 170 and 171: PMS, and bilateral oophorectomy alo
Page 172: 69. Studd J, Leather AT. The need f
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Page 194 and 195: Index Note to index: PMS is used fo
Page 196 and 197: levonorgestrol, with estradiol 156
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