Amenorrhea pathophysiology

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Amenorrhea Microchapters


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Primary amenorrhea
Secondary amenorrhea


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]


Amenorrhea is defined as absence of menstrual cycle. The causes of amenorrhea include hypothalamic, pituitary, thyroid, adrenal, ovarian, uterine, and vaginal. About 25 different genes are involved in the pathogenesis of amenorrhea including 3 different groups of Kallmann syndrome related genes, hypothalamus-pituitary-gonadal (HPG) axis related genes, and obesity related genes. On gross pathology, normal endometrium is the characteristic findings of amenorrhea. Patients of amenorrhea from Craniopharyngioma as have cystic mass filled with motor oil-like fluid on gross pathology. On microscopic histopathological analysis, craniopharyngioma presents as trabecular squamous epithelium surrounded by palisaded columnar epithelium, small-to-medium sized cells with moderate amount of basophilic cytoplasm, bland nuclei, and calcifications. On microscopic histopathological analysis, pituitary adenoma as a cause of amenorrhea presents as loss of fibrous stroma and nested cells of normal anterior pituitary (based on the type of adenoma).


Physiology of normal puberty

Menarche and Menstruation

Hypothalamic-pituitary-ovarian (HPO) axis maturation


Hypothalamic pathogenesis

Pituitary pathogenesis

Thyroid pathogenesis

Adrenal pathogenesis

Ovarian pathogenesis

Uterine pathogenesis


The major genes in amenorrhea

Groups Gene Other name(s) OMIM number Chromosome Function Other related disorders
Kallmann syndrome


Isolated hypogonadotropic hypogonadism[29]

KAL1 KAL1, anosmin-1 308700 Xp22.3
FGFR1 KAL2 136350 8q12
PROKR2 KAL3 607123 20p13
PROK2 KAL4 607002 3p21.1
CHD7 KAL5 608892 8q12.1
FGF8 KAL6 600483 10q24
GPR54 KISS1R 604161 19p13.3
  • Regulation of GnRH secretion
KISS1 KISS1, kisspeptin1 603286 1q32 -
HS6ST1 - 604846 2q21 -
TAC3 NKB 162330 12q13–q21
TACR3 NK3R 152332 4q25
GnRH1 - 152760 8p21–8p11.2
  • One of the most important elements in HPG axis
GnRHR - 138850 4q21.2
NELF - 608137 9q34.3 -
EBF2 - 609934 8p21.2
  • Effective role in HPG axis
HPG axis development DAX1 NR0B 300473 Xp21.2
SF-1 NR5A1 184757 9q33.3
HESX-1 RPX 601802 3p14.3
LHX3 LIM3 600577 9q34.3
PROP-1 - 601538 5q35.3
Obesity related

hypogonadotropic hypogonadism

LEP OB 164160 7q32.1
LEPR OBR 601007 1p31.3
PC1 NEC1 162150 5q15

Abbreviations (alphabetic):
CHD7: Chromodomain helicase DNA-binding protein 7 gene, DAX1: DSS-AHC on the X-chromosome 1, EBF2: Early B-cell factor 2 gene, FGF8: Fibroblast growth factor 8 gene, FGFR1: Fibroblast growth factor receptor 1 gene, FSH: Follicle stimulating hormone, GnRH: Gonadotropin releasing hormone, GnRH1: Gonadotropin releasing hormone 1 gene, GnRHR: Gonadotropin releasing hormone receptor gene, GPR54: G protein-coupled receptor-54 gene, HESX-1: Homeobox gene 1, HPG axis: Hypothalamus-pituitary-gonadal axis, HS6ST1: Heparan sulfate 6-O-sulphotransferase 1 gene, KAL1: Kallmann syndrome 1 gene, LEP: Leptin gene, LEPR: Leptin receptor gene, LH: Luteinizing hormone, LHX3: LIM homeobox gene 3, NEC1: Neuroendocrine convertase 1, NELF: Nasal embryonic LH-releasing hormone factor gene, NK3R: Neurokinin 3 receptor gene, NKB: Neurokinin B gene, NR0B: Nuclear receptor 0B, NR5A1: Nuclear receptor 5A1, OMIM: Online Mendelian Inheritance in Man, PC1: Proprotein convertase 1, PROK2 : Prokineticin 2 gene, PROKR2: Prokineticin 2 receptor gene, PROP-1: PROP paired-like homeobox 1, RPX: Rathke pouch homeobox, SF-1: Steroidogenic factor 1, TAC3: Tachykinin 3 gene,TACR3: Tachykinin 3 receptor gene,

Kisspeptin system (KISS1R and KISS1)

Kallmann syndrome 1 (KAL1)

Fibroblast growth factor receptor 1 and fibroblast growth factor 8 (FGFR1 and FGF8)

Heparan sulfate 6-O-sulphotransferase 1 (HS6ST1)

Prokineticin 2 and prokineticin 2 receptor (PROK2 and PROKR2)

Tachykinin 3 and tachykinin 3 receptor (TAC3 and TACR3)

Gonadotropin releasing hormone and its receptor (GnRH1 and GnRHR)

Chromodomain helicase DNA-binding protein 7 (CHD7)

Nasal embryonic LH-releasing hormone factor (NELF)

Early B-cell factor 2 (EBF2)

DSS-AHC on the X-chromosome 1 (DAX1)

Steroidogenic factor 1 (SF1)

Homeobox gene 1 (HESX1)

LIM homeobox gene 3 (LHX3)

PROP paired-like homeobox 1 (PROP1)

Leptin and leptin receptor (LEP and LEPR)

Proprotein convertase 1 (PC1)

Makorin RING-finger protein 3 (MKRN3)

Estrogen receptor α (ESR1)

Associated Conditions

The associated conditions that are related to amenorrhea, are as following:[75]

Associated conditions
Primary amenorrhea
Secondary amenorrhea
Functional amenorrhea
Kallmann syndrome
Turner syndrome
Noonan syndrome
Gonadal dysgenesis
Chemotherapy/Radiation therapy
Autoimmune oophiritis
Lyase deficiency
Congenital lipoid adrenal hyperplasia
Androgen insensitivity
Congenital hypopituitarism
Bardet-Biedl syndrome
CHARGE syndrome
Gaucher disease
Septo-optic dysplasia
Cystic Fibrosis
Langerhans cell histiocytosis
Rathke pouch cyst
• Isolated hypogonadotropic hypogonadism
HPO axis development disturbance
• Post central nervous system Infection
Chemotherapy/Radiation therapy
Inflammatory bowel disease
Celiac disease
Juvenile rheumatoid arthritis
Sickle cell disease
Chronic renal disease
Diabetes mellitus
Growth hormone deficiency
Cushing syndrome
• Excessive exercise
Anorexia nervosa

Gross Pathology

Gross pathology of craniopharyngioma in third ventricle brain, biphasic mixture - Source: Librepathology

Microscopic Pathology


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