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=== Kisspeptin system (KISS1R and KISS1) === | === Kisspeptin system (KISS1R and KISS1) === | ||
* The GPR54 [[gene]], also called KISS1R, with [[Online Mendelian Inheritance in Man|Online Mendelian Inheritance in Man (OMIM)]] number of 604161 is on chromosome 19p13.3. The KISS1 gene, also | * The GPR54 [[gene]], also called KISS1R, with [[Online Mendelian Inheritance in Man|Online Mendelian Inheritance in Man (OMIM)]] number of 604161 is on chromosome 19p13.3. The KISS1 gene, also known as [[Kisspeptin|kisspeptin1]], with [[OMIM]] number of 603286 is on [[chromosome]] 1q32, | ||
* | * [[kisspeptin]] and related [[G-protein coupled receptor]] (KISS1R or GPR54) have key roles in regulation of [[GnRH]] secretion. The [[GnRH]] secretion has to be pulsatile to stimulate [[gonadotropins]]. [[Kisspeptin|Kisspeptins]] are encoded by KISS1 gene, [[neuropeptides]] secreted from [[hypothalamus]] nuclei. It is found that patients with idiopathic [[hypogonadotropic hypogonadism]] have KISS1 receptor (GPR54) inactivating [[gene]] [[mutations]].<ref name="pmid12944565">{{cite journal |vauthors=de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E |title=Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=19 |pages=10972–6 |year=2003 |pmid=12944565 |pmc=196911 |doi=10.1073/pnas.1834399100 |url=}}</ref><ref name="SeminaraMessager2003">{{cite journal|last1=Seminara|first1=Stephanie B.|last2=Messager|first2=Sophie|last3=Chatzidaki|first3=Emmanouella E.|last4=Thresher|first4=Rosemary R.|last5=Acierno|first5=James S.|last6=Shagoury|first6=Jenna K.|last7=Bo-Abbas|first7=Yousef|last8=Kuohung|first8=Wendy|last9=Schwinof|first9=Kristine M.|last10=Hendrick|first10=Alan G.|last11=Zahn|first11=Dirk|last12=Dixon|first12=John|last13=Kaiser|first13=Ursula B.|last14=Slaugenhaupt|first14=Susan A.|last15=Gusella|first15=James F.|last16=O'Rahilly|first16=Stephen|last17=Carlton|first17=Mark B.L.|last18=Crowley|first18=William F.|last19=Aparicio|first19=Samuel A.J.R.|last20=Colledge|first20=William H.|title=TheGPR54Gene as a Regulator of Puberty|journal=New England Journal of Medicine|volume=349|issue=17|year=2003|pages=1614–1627|issn=0028-4793|doi=10.1056/NEJMoa035322}}</ref> | ||
* By the time of [[puberty]], the KISS1 genes become activated through [[neuroanatomical]] and functional changes from environmental triggers, critical for [[brain]] sexual [[maturation]] and HPG activation with pulsatile [[GnRH]].<ref name="pmid23015158">{{cite journal| author=Kaur KK, Allahbadia G, Singh M| title=Kisspeptins in human reproduction-future therapeutic potential. | journal=J Assist Reprod Genet | year= 2012 | volume= 29 | issue= 10 | pages= 999-1011 | pmid=23015158 | doi=10.1007/s10815-012-9856-1 | pmc=3492584 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23015158 }}</ref> | * By the time of [[puberty]], the KISS1 genes become activated through [[neuroanatomical]] and functional changes from environmental triggers, critical for [[brain]] sexual [[maturation]] and HPG activation with pulsatile [[GnRH]].<ref name="pmid23015158">{{cite journal| author=Kaur KK, Allahbadia G, Singh M| title=Kisspeptins in human reproduction-future therapeutic potential. | journal=J Assist Reprod Genet | year= 2012 | volume= 29 | issue= 10 | pages= 999-1011 | pmid=23015158 | doi=10.1007/s10815-012-9856-1 | pmc=3492584 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23015158 }}</ref> | ||
* Along HPG axis [[neurons]], [[gamma-aminobutyric acid]] is [[inhibitory]] and [[glutamate]] is [[Excitatory neurotransmitter|excitatory neurotransmitters]]. In related KNDy [[neurons]] in [[arcuate nucleus]], the materials secreted are included [[kisspeptin]], [[neurokinin B]], and [[dynorphin A]]. Before the [[puberty]] begins, inhibitory [[dynorphin A]] is the dominant element; decreased by stimulatory effect of [[neurokinin B]], when [[puberty]] started. Conclusively, [[kisspeptin]] and [[GnRH]]/[[LH]] are increased.<ref name="UenoyamaTsukamura2014">{{cite journal|last1=Uenoyama|first1=Yoshihisa|last2=Tsukamura|first2=Hiroko|last3=Maeda|first3=Kei-ichiro|title=KNDy neuron as a gatekeeper of puberty onset|journal=Journal of Obstetrics and Gynaecology Research|volume=40|issue=6|year=2014|pages=1518–1526|issn=13418076|doi=10.1111/jog.12398}}</ref> | * Along HPG axis [[neurons]], [[gamma-aminobutyric acid]] is [[inhibitory]] and [[glutamate]] is [[Excitatory neurotransmitter|excitatory neurotransmitters]]. In related KNDy [[neurons]] in [[arcuate nucleus]], the materials secreted are included [[kisspeptin]], [[neurokinin B]], and [[dynorphin A]]. Before the [[puberty]] begins, inhibitory [[dynorphin A]] is the dominant element; decreased by stimulatory effect of [[neurokinin B]], when [[puberty]] started. Conclusively, [[kisspeptin]] and [[GnRH]]/[[LH]] are increased.<ref name="UenoyamaTsukamura2014">{{cite journal|last1=Uenoyama|first1=Yoshihisa|last2=Tsukamura|first2=Hiroko|last3=Maeda|first3=Kei-ichiro|title=KNDy neuron as a gatekeeper of puberty onset|journal=Journal of Obstetrics and Gynaecology Research|volume=40|issue=6|year=2014|pages=1518–1526|issn=13418076|doi=10.1111/jog.12398}}</ref> | ||
=== Kallmann syndrome 1 (KAL1) === | === Kallmann syndrome 1 (KAL1) === | ||
* The [[KAL1 gene|KAL1]] [[gene]], also called [[anosmin-1]], with [[OMIM]] number of 308700 is on [[chromosome]] Xp22.3, | * The [[KAL1 gene|KAL1]] [[gene]], also called [[anosmin-1]], with [[OMIM]] number of 308700 is on [[chromosome]] Xp22.3, and encodes an [[Extracellular matrix protein|extracellular matrix glycoprotein]]. | ||
* [[Anosmin-1]] is expressed at five weeks of [[gestation]] in [[forebrain]] | * [[Anosmin-1]] is expressed at five weeks of [[gestation]] in [[forebrain]] near [[olfactory bulbs]] and stimulate the [[afferent fibers]] projections around it.<ref name="pmid10340754">{{cite journal |vauthors=Hardelin JP, Julliard AK, Moniot B, Soussi-Yanicostas N, Verney C, Schwanzel-Fukuda M, Ayer-Le Lievre C, Petit C |title=Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome |journal=Dev. Dyn. |volume=215 |issue=1 |pages=26–44 |year=1999 |pmid=10340754 |doi=10.1002/(SICI)1097-0177(199905)215:1<26::AID-DVDY4>3.0.CO;2-D |url=}}</ref> | ||
* [[X-linked]] [[Kallman syndrome|Kallmann syndrome]] is directly associated with [[KAL1 gene|KAL1]] deletion. It is assumed to result in an absence of [[Olfactory system|olfactory fibers]] along with disturbed migration of [[GnRH]] [[neurons]], supposed to form from migrated [[olfactory placode]].<ref name="pmid2687610">{{cite journal |vauthors=Schwanzel-Fukuda M, Bick D, Pfaff DW |title=Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome |journal=Brain Res. Mol. Brain Res. |volume=6 |issue=4 |pages=311–26 |year=1989 |pmid=2687610 |doi= |url=}}</ref> | * [[X-linked]] [[Kallman syndrome|Kallmann syndrome]] is directly associated with [[KAL1 gene|KAL1]] deletion. It is assumed to result in an absence of [[Olfactory system|olfactory fibers]] along with disturbed migration of [[GnRH]] [[neurons]], supposed to form from migrated [[olfactory placode]].<ref name="pmid2687610">{{cite journal |vauthors=Schwanzel-Fukuda M, Bick D, Pfaff DW |title=Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome |journal=Brain Res. Mol. Brain Res. |volume=6 |issue=4 |pages=311–26 |year=1989 |pmid=2687610 |doi= |url=}}</ref> | ||
* Male patient with [[KAL1 gene|KAL1]] [[mutation]] would have central [[hypogonadism]] and [[anosmia]]/[[hyposmia]]. Additionally, the more [[diseases]] are assumed to relate with [[KAL1 gene]], such as midline [[facial]] defects ([[cleft lip]] and/or [[cleft palate]]), short [[metacarpals]], [[renal agenesis]], [[sensorineural hearing loss]], bimanual [[synkinesis]], [[oculomotor]] abnormalities, and [[cerebellar ataxia]].<ref name="pmid17624596">{{cite journal |vauthors=Trarbach EB, Silveira LG, Latronico AC |title=Genetic insights into human isolated gonadotropin deficiency |journal=Pituitary |volume=10 |issue=4 |pages=381–91 |year=2007 |pmid=17624596 |doi=10.1007/s11102-007-0061-7 |url=}}</ref> | * Male patient with [[KAL1 gene|KAL1]] [[mutation]] would have central [[hypogonadism]] and [[anosmia]]/[[hyposmia]]. Additionally, the more [[diseases]] are assumed to relate with [[KAL1 gene]], such as midline [[facial]] defects ([[cleft lip]] and/or [[cleft palate]]), short [[metacarpals]], [[renal agenesis]], [[sensorineural hearing loss]], bimanual [[synkinesis]], [[oculomotor]] abnormalities, and [[cerebellar ataxia]].<ref name="pmid17624596">{{cite journal |vauthors=Trarbach EB, Silveira LG, Latronico AC |title=Genetic insights into human isolated gonadotropin deficiency |journal=Pituitary |volume=10 |issue=4 |pages=381–91 |year=2007 |pmid=17624596 |doi=10.1007/s11102-007-0061-7 |url=}}</ref> | ||
Revision as of 17:46, 18 October 2017
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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]
Overview
Amenorrhea is defined as absence of menstrual cycle. The pathophysiology of amenorrhea include hypothalamic, pituitary, thyroid, adrenal, ovarian, uterine, and vaginal causes. About 25 various genes are involved in pathogenesis of amenorrhea such as 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 characteristic findings of amenorrhea. Patients of amenorrhea from Craniopharyngioma 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 presents as loss of fibrous stroma and nested cells of normal anterior pituitary (based on the type of adenoma).
Pathophysiology
Physiology of normal puberty
Menarche and Menstruation
- The mean age for onset of menstruation is 12.43 years in US. About 80% of females experience menarche between 11 and 13.75 years of age.[1]
- Almost all (98%) of females experience menarche by the age of 15.[2]
- Gonadotropin releasing hormone (GnRH) is the main factor in puberty onset.
- GnRH is secreted by the neurosecretory neurons of hypothalamus into the hypophysial portal system, from where it is transferred to anterior pituitary gland.
- GnRH stimulates production and secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH).
- During puberty the amplitude and frequency of GnRH pulses is significantly increased.
- GnRH secretion is regulated by certain neurotransmitters in brain, such as dopamine, endogenous opioids, norepinephrine, gamma amino butyric acid (GABA), and corticotropin releasing hormone (CRH). Alteration in level and function of these neurotransmitters may lead to specific types of amenorrhea. For example stress, exercise, and malnutrition affects CRH, β-endorphin, and dopamine, respectively.[3]
- The main trigger for puberty onset is not completely understood. After puberty onset, the negative feedback on GnRH is removed. Then, pulsatile GnRH secretion induce LH and FSH production which finally lead to ovulation. In the absence of pregnancy, the follicle is turned to corpus luteum. Endometrium proliferates through estrogen release from corpus luteum. Withdrawal of progesterone from estrogen-mediated proliferated endometrium will result in menstrual bleeding.
Hypothalamic-pituitary-ovarian (HPO) axis maturation
- After activation of the HPO axis during 2nd trimester of pregnancy, level of gonadotropins peak from mid to term pregnancy. After inhibition of placental hormones' feedback, FSH and LH will increase slightly to mild secondary peak.
- Negative feedback from adrenal androgens keep the gonadotropins in low plasma level until puberty.[4]
- Right before puberty, the sensitivity of hypothalamus to adrenal androgens' negative feedback is decreased. This leads to increased production of GnRH and make it possible for GnRH to be raised in magnitude and frequency to induce an increase in LH and FSH.[5]
- The complete maturation of HPO axis takes around 5-7 years from menstruation onset. Generally, during the first two years of menstruation, the cycles are mostly anovulatory.
Pathogenesis
- Amenorrhea is defined as absence of menstrual cycle. Primary amenorrhea is absence of menstruation from the beginning of puberty, while secondary amenorrhea is disrupting the menstrual cycles after several normal cycles.[3]
- The pathophysiology of amenorrhea is multifactorial and include hypothalamic, pituitary, thyroid, adrenal, ovarian, uterine, and vaginal pathogenesis.
Hypothalamic pathogenesis
- The most common cause of amenorrhea in adolescents is hypothalamic disorders and known as hypothalamic amenorrhea.
- In the initial 2-3 years after menarche onset, the HPO axis is still developing. Immature HPO axis may lead to anovulatory cycles which can cause abnormalities in menstrual cycles.
- The most common cause of amenorrhea after 2-3 years of puberty onset include eating disorders, excessive exercise, medications, and psychosocial stress.[6][7]
- Leptin plays an important role in energy consumption, body composition, food intake along with sexual maturation and reproductive improvement.
- It is assumed that leptin has a role in the development of hypothalamic amenorrhea.
- Leptin receptors are in close relationship with hypothalamus and it is postulated that leptin regulates GnRH production and secretion.
- The main reason of amenorrhea in patients with anorexia nervosa or excessive exercise is down-regulation of leptin receptors, which is elevated by refeeding.[8][9][10]
- Leptin level in cachexic patients will increase after gaining appropriate weight in normal people, but will remain low in patients with amenorrhea.[11][12]
- It has been observed that leptin levels in amenorrheic athletes are low as compared to non-athletes women or athletes with regular menses.[13][14]
- Administration of recombinant leptin for 3 months in women with conditions such as hypothalamic amenorrhea, excessive exercises or weight loss has been associated with an increased level of LH, FSH, and estradiol and led to ovulatory cycles.[15]
- Antipsychotic drugs and other medications that have inhibitory effect on dopamine D2 receptor leads to an increased level of prolactin. Higher levels of prolactin suppress pulsatile GnRH and block positive feedback of estradiol on hypothalamus, leading to disruption of HPO axis.[16]
- Stress and strenuous activities llike other metabolic or cardiovascular responses are regulated through corticotropin releasing hormone (CRH), secreted by paraventricular nuclei of hypothalamus. CRH induce the release of β-endorphin, an endogenous opioid. Both CRH and β-endorphin suppress GnRH release. On the other hand, glucocorticoids suppress LH production from pituitary and also estrogen/progesterone from ovaries.[17]
- Kallmann syndrome, a genetic disorder caused by KAL gene mutation, has disturbance in migration of olfactory nerves along with GnRH neurons. Lack of GnRH leads to absence of secondary sexual characteristics and amenorrhea.[18]
Pituitary pathogenesis
- One of the most prevalent anterior pituitary tumors is prolactinoma. Prolactinoma leads to increased prolactin secretion and along with the tumor's mass effect may cause suppression of GnRH.
- Second prevalent tumor in suprasellar region is craniopharyngioma. The tumor leads to LH and FSH disturbances, which may cause amenorrhea.[19]
Thyroid pathogenesis
- In hypothyroidism, the main mechanism that can lead to amenorrhea is the influence of thyrotropin releasing hormone (TRH) on lactotroph cells, increasing prolactin levels. Since the TRH is increased in hypothyroidism, it leads to functional hyperprolactinemia. The increase in prolactin may suppress the GnRH pulsatility and lead to amenorrhea.[20]
- In hyperthyroidism, the mechanism of amenorrhea is not clear. It is assumed that increased level of sex hormone binding globulins (SHBGs) in hyperthyroidism may lead to increased levels of androgens and estrogen. Conclusively, the LH surge become absent and amenorrhea happens.[21]
Adrenal pathogenesis
- Congenital adrenal hyperplasia (CAH) is a group of genetic enzyme deficiency in adrenal gland. Most common the defect is in 21-hydroxylase enzyme, which leads to decrease in the level of aldosterone and cortisol. To overcome the hormone deficiency, CRH production is increased by hypothalamus. As mentioned before, increased level of CRH may suppress GnRH and lead to amenorrhea.[22]
- Cushing syndrome has an increased level of cortisol, that can directly inhibit HPO axis and lead to amenorrhea.
Ovarian pathogenesis
- In polycystic ovary syndrome (PCOS) insulin resistance leads to increased androgen production (insulin reduces the SHBG circulating in plasma, causing increased testosterone). In ovaries, increased stimulation from GnRH leads to increased production of 17-hydroxy progesterone and cytochrome P450c17 which promotes androgens biosynthesis.[23][24] Finally, the pulsatility of GnRH will be disrupted leading to amenorrhea .[25]
- Primary ovarian insufficiency is multifactorial and leads to ovarian failure and decrease in estrogen. In galactosemia, it is assumed that galactose and its metabolites are toxic to ovarian tissue.[26]
Uterine pathogenesis
- The main pathogenesis of amenorrhea in androgen insensitivity syndrome is the absence of uterus. The patient is genotypically male, 46 XY; but with absent sexual characteristics due to lack of functional effect of androgen hormones on their receptors.
- One of the acquired conditions that can lead to amenorrhea is Asherman syndrome. The base of this syndrome is any condition that can harm the endometrium, such as scarring from surgical procedure or adhesion from severe infection.
- Mayer-Rokitansky-Kuster-Hauser syndrome is complete agenesis of uterine, blind ended vagina. The lack of uterine and endometrium is the main pathogenesis of amenorrhea. The main reason of uterine agenesis is overactivation of anti-mullerian hormone in embryogenesis period.[27] Cervical agenesis also follow the similar process.
- Imperforated hymen, transverse vaginal septum, and vaginal agenesis are other anatomical disorders of female reproductive system that can lead to amenorrhea.[28]
Genetics
The major genes in amenorrhea
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,
| Groups | Gene | Other name(s) | OMIM number | Chromosome | Function | Other related disorders |
|---|---|---|---|---|---|---|
| Kallmann syndrome
and 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 |
|
- | |
| KISS1 | KISS1, kisspeptin1 | 603286 | 1q32 |
|
- | |
| HS6ST1 | - | 604846 | 2q21 |
|
- | |
| TAC3 | NKB | 162330 | 12q13–q21 |
|
||
| TACR3 | NK3R | 152332 | 4q25 | |||
| GnRH1 | - | 152760 | 8p21–8p11.2 |
|
| |
| GnRHR | - | 138850 | 4q21.2 |
|
||
| NELF | - | 608137 | 9q34.3 | - | ||
| EBF2 | - | 609934 | 8p21.2 |
|
- | |
| 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 |
|
|
Kisspeptin system (KISS1R and KISS1)
- The GPR54 gene, also called KISS1R, with Online Mendelian Inheritance in Man (OMIM) number of 604161 is on chromosome 19p13.3. The KISS1 gene, also known as kisspeptin1, with OMIM number of 603286 is on chromosome 1q32,
- kisspeptin and related G-protein coupled receptor (KISS1R or GPR54) have key roles in regulation of GnRH secretion. The GnRH secretion has to be pulsatile to stimulate gonadotropins. Kisspeptins are encoded by KISS1 gene, neuropeptides secreted from hypothalamus nuclei. It is found that patients with idiopathic hypogonadotropic hypogonadism have KISS1 receptor (GPR54) inactivating gene mutations.[30][31]
- By the time of puberty, the KISS1 genes become activated through neuroanatomical and functional changes from environmental triggers, critical for brain sexual maturation and HPG activation with pulsatile GnRH.[32]
- Along HPG axis neurons, gamma-aminobutyric acid is inhibitory and glutamate is excitatory neurotransmitters. In related KNDy neurons in arcuate nucleus, the materials secreted are included kisspeptin, neurokinin B, and dynorphin A. Before the puberty begins, inhibitory dynorphin A is the dominant element; decreased by stimulatory effect of neurokinin B, when puberty started. Conclusively, kisspeptin and GnRH/LH are increased.[33]
Kallmann syndrome 1 (KAL1)
- The KAL1 gene, also called anosmin-1, with OMIM number of 308700 is on chromosome Xp22.3, and encodes an extracellular matrix glycoprotein.
- Anosmin-1 is expressed at five weeks of gestation in forebrain near olfactory bulbs and stimulate the afferent fibers projections around it.[34]
- X-linked Kallmann syndrome is directly associated with KAL1 deletion. It is assumed to result in an absence of olfactory fibers along with disturbed migration of GnRH neurons, supposed to form from migrated olfactory placode.[35]
- Male patient with KAL1 mutation would have central hypogonadism and anosmia/hyposmia. Additionally, the more diseases are assumed to relate with KAL1 gene, such as midline facial defects (cleft lip and/or cleft palate), short metacarpals, renal agenesis, sensorineural hearing loss, bimanual synkinesis, oculomotor abnormalities, and cerebellar ataxia.[36]
Fibroblast growth factor receptor 1 and fibroblast growth factor 8 (FGFR1 and FGF8)
- The FGFR1 gene, also called KAL2, with OMIM number of 136350 is on chromosome 8q12, encode a receptor tyrosine kinase protein. The FGF8 gene, also called KAL6, is on chromosome 10q24.
- FGFR1 pathway is assumed to be the main role in embryogenesis, homeostasis, and wound healing. FGF8 critical role in primary generation of neural tissue has been established by so many researchers.[37]
- On the other hand, interaction between FGFR1, FGF8, and heparan sulfate helps olfactory bulb to become differentiated and developed, also facilitates GnRH neurons migration and function.[38]
- Dominant deletion mutation of FGFR1 gene is found to cause a 30% decrease in hypothalamic GnRH neurons.[39] Other defects related to FGFR1 are including cleft palate or lip, dental agenesis and bimanual synkinesis.[36] Other disorders related to FGF8 are including cardiac, craniofacial, forebrain, midbrain, and cerebellar developmental abnormalities.
Heparan sulfate 6-O-sulphotransferase 1 (HS6ST1)
- The HS6ST1 gene with OMIM number of 604846 is on chromosome 2q21, has some functions in extracellular sugar modifications; but has already found mutated in hypogonadism.[40]
- The modifications of heparan sulfate polysaccharides in extracellular matrix have some roles in FGFR-FGF and also anosmin1-cell membrane interactions.[41][42]
- This gene has been found mutated in both Kallmann syndrome and idiopathic hypogonadism, with various course and timing or GnRH deficiencies.[40]
Prokineticin 2 and prokineticin 2 receptor (PROK2 and PROKR2)
- The PROK2 and PROKR2 genes, also called KAL4 and KAL3, with OMIM numbers of 607002 and 607123 are on chromosomes 3p21.1 and 20p13, respectively. They are believed to be cause of Kallmann syndrome.
- PROKR2 is a G protein coupled receptor (GPCR), has a major role in olfactory bulb development; the mutation may lead to severe gonadal atrophy.[43]
- In prokineticin system, there are two receptors (PROKR1 and PROKR2) and two ligands (PROK1 and PROK2). PROK1 and its receptor (PROKR1) have some roles in gastrointestinal system motility. However, PROK2 and PROKR2 are parts of neuroendocrine system, located in arcuate nucleus, olfactory tract, and suprachiasmatic nucleus.[44]
- It seems that mutated versions of PROK2 and PROKR2 could lead to decrease GnRH production and hypogonadism. Other disorders caused by their mutations are including fibrous dysplasia, sleep disorder, severe obesity, synkinesis, and epilepsy.[45]
Tachykinin 3 and tachykinin 3 receptor (TAC3 and TACR3)
- The TAC3 and TACR3 genes, also called neurokinin B (NKB) and neurokinin 3 receptor (NK3R), with OMIM numbers of 162330 and 152332, are on chromosomes 12q13–q21 and 4q25, respectively.[46]
- During the surveys, it has found that normal function of TAC3/TACR3 system is necessary for an intact HPG axis and also its development during puberty. On the other hand, TAC3/TACR3 system disturbance is declared to cause micropenis and also cryptorchidism in males, showing the major role in fetal gonadotropins secretion.[47]
- TACR3 encoded protein (NK3R) is GPCR, initially produced in central nervous system. The major mechanism, through which the mutated gene may lead to neuroendocrine disturbance and delayed puberty, is not completely discovered.[48]
- TAC3 encoded protein (NKB) is produced in arcuate nucleus of hypothalamus and play an important role in GnRH secretion. Parallel to that, kisspeptin is also produced and secreted in arcuate nucleus, whereas, both of them inhibited by estrogen. It may be considered that kisspeptin and NKB have same roles in diverting negative feedback from sex hormones to GnRH. Their mutation showed to related with hypogonadism.
Gonadotropin releasing hormone and its receptor (GnRH1 and GnRHR)
- The GnRH1 and GnRHR genes with OMIM numbers of 152760 and 138850 are on chromosomes 8p21–8p11.2 and 4q21.2, respectively.[49]
- In HPG axis, GnRH is one of the most effective elements; therefore, its defect could directly influence the axis and slow down the progress. Mutated gene in mice make them sexually infantile, infertile, and with low sex hormones and gonadotropins.[50]
- The GnRHR gene is also responsible for gonadal normal functions, its mutation could lead to hypogonadism and delayed puberty. It seems that the mutation has other outcomes, such as atrophic gonads along with low LH/FSH and sex hormones, sexual puberty disturbance, inability to conceive, and failure to impact from exogenous GnRH. [51]
- These genes variable expressivity could cause spectrum of symptoms, from fertile eunuch syndrome and partial idiopathic hypogonadotropic hypogonadism to complete GnRH resistance (i.e., characterized by cryptorchidism), microphallus, very low LH/FSH, and delayed puberty.[52]
- The other disorders that have found to be related to GnRH mutation are including tooth abnormal maturation and biomineralization.[53]
Chromodomain helicase DNA-binding protein 7 (CHD7)
- The CHD7 gene, also called as KAL5, with OMIM number of 608892 is on chromosome 8q12.1.
- The main result of the CHD7 gene mutation is autosomal dominant CHARGE syndrome, combination of hypogonadism and Kallmann syndrome, which included:[54]
- Colobomata
- Heart anomalies
- Choanal Atresia
- Retardation
- Genital anomalies
- Ear anomalies
- In patients with hypogonadism or Kallmann syndrome with specific features, such as semicircular canals hypoplasia or aplasia, dysmorphic ears, and also deafness, would be better to screen for CHD7 gene situation.
Nasal embryonic LH-releasing hormone factor (NELF)
- The NELF gene with OMIM number of 608137 is on chromosome 9q34.3; it is mostly in nervous tissues specifically during fetal development and also may be found in olfactory bulb and pituitary LH releasing cells.
- The most common function is in olfactory axons and also GnRH neurons, before and during neuron migration in developmental process.[55]
- It is assumed to has some relations with Kallmann syndrome. [56]
Early B-cell factor 2 (EBF2)
- The EBF2 gene with OMIM number of 609934 is on chromosome 8p21.2; mostly expressed in mice osteoblasts and osteoclast cells.[57]
- The gene is believed to has an effective role in HPG axis. In mutated version, it can cause defect in the axis, leading to secondary hypogonadism.[58]
DSS-AHC on the X-chromosome 1 (DAX1)
- The DAX1 gene, also called nuclear receptor 0B (NR0B), with OMIM number of 300473 is on chromosome Xp21.2, mostly expressed in all members of HPG axis (hypothalamus, pituitary, and gonads).[59]
- During the spermatogenesis and steroidogenesis, it seems that both sertoli and leydig cells have increased the expression of DAX1 gene. It is assumed that during puberty, the peak expression of DAX1 occurred.[60]
- Other disease that can be caused by DAX1 mutation is congenital adrenal cortex hypoplasia.[61]
Steroidogenic factor 1 (SF1)
- The SF1 gene, also called nuclear receptor 5A1 (NR5A1), with OMIM number of 184757 is on chromosome 9q33.3, has some roles in reproduction, steroidogenesis, and sexual differentiation.
- It is mainly expressed in sertoli and leydig cells, plays an important role in steroidogenesis and spermatogenesis. The SF1 is believed to experience increase in expression during childhood into adolescence, become dominantly expressed by leydig cells in puberty.[60]
- It seems that other diseases can be caused by SF1 mutation, such as male pseudohermaphroditism, Denys-Drash syndrome, and also hypospadias.[62]
Homeobox gene 1 (HESX1)
- The HESX1 gene, also called Rathke pouch homeobox (RPX), with OMIM number of 601802 is on chromosome 3p14.3, starts to express during embryogenesis and help the formation of Rathke pouch and anterior pituitary.[63]
- The main function of HESX1 gene is pituitary development and also midfacial differentiation. Mutation may lead to pituitary hypoplasia and decreased level of all anterior pituitary hormones.[64]
- Other disorders resulting from HESX1 mutation are including septooptic dysplasia, reduced prosencephalon, anophthalmia, microphthalmia, defective olfactory development, Rathke pouch bifurcations, and also abnormalities in the corpus callosum, hippocampus, and septum pellucidum.[63]
LIM homeobox gene 3 (LHX3)
- The LHX3 gene, also called LIM3, with OMIM number of 600577 is on chromosome 9q34.3, mainly expressed in developing anterior pituitary gland.[65]
- It seems that LHX3 gene function is very important in development of pituitary gland and its hormone secretion. Therefore, mutation in the gene is related to combined pituitary hormone deficiency (CPHD).[66]
- The LHX3 gene mutation can also result in neonatal hypoglycemia, short neck with limited rotation, mild sensorineural hearing loss, skin laxity, and skeletal abnormalities.[65]
PROP paired-like homeobox 1 (PROP1)
- The PROP1 gene with OMIM number of 601538 is on chromosome 5q35.3, with a main rule in developing anterior pituitary gland and also proper development of gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs.[67]
- When PROP1 gene become inactivated through mutation, patient may experience deficiency in LH, FSH, GH, TSH, and prolactin serum levels. Lack of LH and FSH would prevent the patient entering the puberty.[68]
- Regarding the gene function in different cell types of pituitary, it can be concluded that the PROP1 gene mutation can lead to thyroid dysfunctions, growth retardation, and libido/lactation problems.
Leptin and leptin receptor (LEP and LEPR)
- The LEP and LEPR genes, also called OB and OBR, with OMIM numbers of 164160 and 601007 are on chromosomes 7q32.1 and 1p31.3, respectively; both of them have major roles in modulation of body weight.
- These genes are believed to carry the message of beginning the puberty, recombinant leptin injection in female mice may result in puberty and also cure their maturation problems.[69]
- It seems that leptin level in human beings become increased about 50% just before puberty and also during the puberty.[70]
- Mutation in these genes may also result in disorders in hematopoiesis, angiogenesis, wound healing, and the immune or inflammatory response.
Proprotein convrtase 1 (PC1)
- The PC1 gene, also called neuroendocrine convertase 1 (NEC1), with OMIM number of 162150 is on chromosome 5q15, mainly regulates neuroendocrine pathway.
- PC1 gene has the dramatic role of proopiomelanocortin (POMC) cleavage. On the other hand, they help processing proinsulin and proglucagon in pancreas.[71]
- There is assumed relationship between PC1 gene mutation and hypogonadotropic hypogonadism along with extreme childhood obesity, abnormal glucose homeostasis, hypocortisolism, elevated plasma proinsulin, and also POMC concentrations.[72]
Makorin RING-finger protein 3 (MKRN3)
- Newly discovered MKRN3 gene has a role in ubiquitination and cell signaling. The gene family proteins are majorly expressed in fetal brain during development, especially in arcuate nucleus.
- It seems that the gene amplification is on its peak after birth, gradually declined by the time, and finally raised again when puberty begins. Therefore, it is believed to be one of the factors of starting the puberty, along with kisspeptins and neurokinin B.[73]
Estrogen receptor α (ESR1)
- Estrogen receptor mutations are very rare, reported as a case report with delayed puberty.[74]
- Estradiol effects on breast maturation and also presents a negative feedback to hypothalamus and pituitary, by means of estrogen receptor α (encoded by ESR1 gene).[75]
- Female mice with mutated ESR1 gene may have hypoplastic uterus plus hemorrhagic, multicystic ovary without corpus luteum; which is make them infertile.[76]
Associated Conditions
The associated conditions that are related to amenorrhea, are as following:[77]
Gross Pathology
- On gross pathology, normal endometrium in proliferative or luteal phases are characteristic findings of amenorrhea.
- In any other cases of amenorrhea secondary to other causes, the related gross pathology is expected.
- Craniopharyngioma gross pathology is cystic mass filled with motor oil-like fluid.[78]
Microscopic Pathology
- On microscopic histopathological analysis, trabecular squamous epithelium surrounded by palisaded columnar epithelium, small-to-medium sized cells with moderate amount of basophilic cytoplasm, bland nuclei, and calcifications are characteristic findings of craniopharyngioma.
- On microscopic histopathological analysis, loss of fibrous stroma and nested cells of normal anterior pituitary (based on the type of adenoma) are characteristic findings of pituitary adenoma.
-
Craniopharyngioma; with psammoma bodies - by Jensflorian source: Librepathology -
Craniopharyngioma; with calcification and two types of epithelium - by Sarahkayb source: Librepathology -
Craniopharyngioma; multicystic texture - by Jensflorian source: Librepathology -
Pituitary adenoma of lactotroph cells (prolactin producing) - by Jensflorian source: Librepathology -
Pituitary adenoma of lactotroph cells (prolactin producing) regression after treatment - by Jensflorian source: Librepathology -
Pituitary adenoma of thyrotroph cells (TSH producing) - by Jensflorian source: Librepathology
References
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<ref>tag; no text was provided for refs namedPalmertDunkel2012 - ↑ Fernandez-Miranda JC, Gardner PA, Snyderman CH, Devaney KO, Strojan P, Suárez C, Genden EM, Rinaldo A, Ferlito A (2012). "Craniopharyngioma: a pathologic, clinical, and surgical review". Head Neck. 34 (7): 1036–44. doi:10.1002/hed.21771. PMID 21584897.