title: Pathophysiological aspects of thyroid hormone disorders/thyroid peroxidase autoantibodies and reproduction.
abstract: BACKGROUND
  Thyroid hormone disorders and thyroid peroxidase autoantibodies (TPO-Ab) in women are associated with subfertility and early pregnancy loss. Here, we aim to provide a comprehensive overview of the literature on the pathophysiology of these associations.
  
  
  METHODS
  A review of the literature in the English language was carried out. Relevant studies were identified by searching Medline, EMBASE and the Cochrane Controlled Trials Register from 1975 until March 2014.
  
  
  RESULTS
  From a total of 6108 primary selected articles from the literature search, 105 articles were selected for critical appraisal. Observational data indicate that altered thyroid hormone levels are associated with disturbed folliculogenesis, spermatogenesis, lower fertilization rates and lower embryo quality. Triiodothyronine (T3) in combination with FSH enhances granulosa cell proliferation and inhibits granulosa cell apoptosis by the PI3K/Akt pathway. T3 is considered a biological amplifier of the stimulatory action of gonadotrophins on granulosa cell function. T3 increases the expression of matrix metalloproteinases (MMP), MMP-2, MMP-3, fetal fibronectin and integrin α5β1T3 in early placental extravillous trophoblasts. Thyroid hormone transporters and receptors are expressed in the ovary, early embryo, endometrium, uterus and placenta. No other data explaining the associations could be retrieved from the literature. The presence of TPO-Ab is negatively associated with spermatogenesis, fertilization and embryo quality, but no data are available on the potential pathophysiological mechanisms.
  
  
  CONCLUSIONS
  Thyroid hormone disorders and TPO-Ab are associated with disturbed folliculogenesis, spermatogenesis, fertilization and embryogenesis. The pathophysiology of these associations remains largely unknown, as evidence is limited and includes studies using small sample sizes, and often restricted to animal models. There are no studies on the pathophysiology underlying the association between TPO-Ab and reproduction. The available evidence, although limited, supports a role of thyroid hormone in fertility and early pregnancy. This justifies clinical intervention studies on the effects of thyroid hormone supplementation in women with subclinical hypothyroidism and in women prone to develop hypothyroidism due to the presence of TPO-Ab. In addition, more research is needed to identify the underlying mechanisms. This would be of particular interest in women undergoing IVF to pinpoint the effects of thyroid hormone on different parameters of reproduction.
authors: Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Academic Medical Centre, Amsterdam, The Netherlands r.vissenberg@amc.uva.nl.
authors: R
authors: R
authors: Vissenberg
authors: Reproductive Biology Laboratory, Academic Medical Centre, Amsterdam, The Netherlands.
authors: V D
authors: VD
authors: Manders
authors: Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors: S
authors: S
authors: Mastenbroek
authors: Department of Endocrinology and Metabolism, Academic Medical Centre, Amsterdam, The Netherlands.
authors: E
authors: E
authors: Fliers
authors: Reproductive Biology Laboratory, Academic Medical Centre, Amsterdam, The Netherlands.
authors: G B
authors: GB
authors: Afink
authors: Reproductive Biology Laboratory, Academic Medical Centre, Amsterdam, The Netherlands Department of Obstetrics and Gynaecology, Academic Medical Centre, Amsterdam, The Netherlands.
authors: C
authors: C
authors: Ris-Stalpers
authors: Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Academic Medical Centre, Amsterdam, The Netherlands.
authors: M
authors: M
authors: Goddijn
authors: Department of Endocrinology and Metabolism, Academic Medical Centre, Amsterdam, The Netherlands.
authors: P H
authors: PH
authors: Bisschop
mesh_terms: D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D049109:Cell Proliferation / Q000502:physiology; D020964:Embryo Loss / Q000276:immunology; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006107:Granulosa Cells / Q000166:cytology; D006801:Humans; D007037:Hypothyroidism / Q000473:pathology*; D007453:Iodide Peroxidase / Q000276:immunology*; D023421:Models, Animal; D006080:Ovarian Follicle / Q000166:cytology / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases; D010920:Placenta / Q000502:physiology; D011247:Pregnancy; D012098:Reproduction / Q000276:immunology / Q000502:physiology; D013091:Spermatogenesis / Q000276:immunology; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D014284:Triiodothyronine; D005640:Follicle Stimulating Hormone; D007453:Iodide Peroxidase; D019869:Phosphatidylinositol 3-Kinases
keywords: embryogenesis; fertility; placentation; thyroid hormone; thyroid peroxidase autoantibodies