Gynecomastia pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Gynecomastia}}
{{Gynecomastia}}
{{CMG}}; {{AE}}  
{{CMG}}; {{AE}} {{HS}}
==Overview==
==Overview==
The main pathophysiology behind gynecomastia is increased estrogen to androgen ratio which can occur through multiple mechanisms. These mechanisms can be physiological, pathological or pharmacological.


==Pathophysiology==
==Pathophysiology==
===Hormones involved in breast development===
*[[Estrogen]] and [[Progesterone|progesteron]]<nowiki/>e act in a coordinated manner to support breast development. [[Estrogen]] helps duct growth and [[progesterone]] promotes [[alveolar]] development which only occurs in female as gynecomastia doesn't have [[alveolar]] development. <ref name="pmid10935020">{{cite journal |vauthors=Bocchinfuso WP, Korach KS |title=Mammary gland development and tumorigenesis in estrogen receptor knockout mice |journal=J Mammary Gland Biol Neoplasia |volume=2 |issue=4 |pages=323–34 |year=1997 |pmid=10935020 |doi= |url=}}</ref><ref name="pmid8248223">{{cite journal |vauthors=Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O |title=Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue=23 |pages=11162–6 |year=1993 |pmid=8248223 |pmc=47942 |doi= |url=}}</ref>
*[[Growth hormone]] which acts through [[IGF-1]] acts as a mediator in the presence of [[estrogen]] and [[progesterone]] for ductal [[Breast|breast duct development]].<ref name="pmid10791764">{{cite journal |vauthors=Kleinberg DL, Feldman M, Ruan W |title=IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis |journal=J Mammary Gland Biol Neoplasia |volume=5 |issue=1 |pages=7–17 |year=2000 |pmid=10791764 |doi= |url=}}</ref> The [[IGF-1]] levels have been found higher in boys with [[Gynecomastia|pubertal gynecomastia]] which shows the role of GH and IGF-1 in the [[pathogenesis]] of [[gynecomastia]].<ref name="pmid24033660">{{cite journal |vauthors=Mieritz MG, Sorensen K, Aksglaede L, Mouritsen A, Hagen CP, Hilsted L, Andersson AM, Juul A |title=Elevated serum IGF-I, but unaltered sex steroid levels, in healthy boys with pubertal gynaecomastia |journal=Clin. Endocrinol. (Oxf) |volume=80 |issue=5 |pages=691–8 |year=2014 |pmid=24033660 |doi=10.1111/cen.12323 |url=}}</ref>
*[[Prolactin]] in the presence of [[estrogen]] and [[progesterone]] also supports [[breast]] development. It also plays an indirect role as it causes [[central hypogonadism]] which alters the [[androgen]]/[[estrogen]] balance.<ref name="pmid25905330">{{cite journal |vauthors=De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Swerdloff RS, Ng JCM |title= |journal= |volume= |issue= |pages= |year= |pmid=25905330 |doi= |url=}}</ref> <ref name="pmid22790552">{{cite journal| author=Barros AC, Sampaio Mde C| title=Gynecomastia: physiopathology, evaluation and treatment. | journal=Sao Paulo Med J | year= 2012 | volume= 130 | issue= 3 | pages= 187-97 | pmid=22790552 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22790552  }} </ref>
*[[Aromatase]] [[catalyzes]] the conversion of [[androgens]] to [[estrogen]] and promotes the [[breast]] development. So, gynecomastia can also result from overexpression of [[aromatase]].<ref name="pmid12239119">{{cite journal| author=Li X, Wärri A, Mäkelä S, Ahonen T, Streng T, Santti R et al.| title=Mammary gland development in transgenic male mice expressing human P450 aromatase. | journal=Endocrinology | year= 2002 | volume= 143 | issue= 10 | pages= 4074-83 | pmid=12239119 | doi=10.1210/en.2002-220181 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12239119  }} </ref><ref name="pmid12736278">{{cite journal| author=Shozu M, Sebastian S, Takayama K, Hsu WT, Schultz RA, Neely K et al.| title=Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene. | journal=N Engl J Med | year= 2003 | volume= 348 | issue= 19 | pages= 1855-65 | pmid=12736278 | doi=10.1056/NEJMoa021559 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12736278  }} </ref>
{{familytree/start}}
{{familytree | | | | | | | | | | |H02| |H02=Breast Tissue}}
{{familytree | | | | |,|-|-|-|-|-|-|^|-|-|-|-|-|-|-|.}}
{{familytree | | | |I01| | | | | | | | | | | | | |I02|I01=Stimulatory Action|I02=Inhibitory Action}}
{{familytree | | | | |!| | | | | | | | | | | | | | |!}}
{{familytree | | | |J01| | | | | | | | | | | | | |J02|J01=Estrogen|J02= Androgens}}
{{familytree | | | | |!| | | | | | | | | | | | | | | }}
{{familytree | | | |J01| | | | | | | | | | | | | | |J01=GH & IGF-1|}}
{{familytree/end}}


===Pathogenesis===
===Pathogenesis===
*It is thought that Gynecomastia can result from any condition, drugs or disease state that causes an increase in circulating estrogen, decrease in androgen or the sensitivity of the breast tissue to the circulating estrogen.<ref name="pmid25905330">{{cite journal |vauthors=De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Swerdloff RS, Ng JCM |title= |journal= |volume= |issue= |pages= |year= |pmid=25905330 |doi= |url=}}</ref>
*It is thought that [[gynecomastia]] can result from any condition, [[drug]] or disease state that causes an increase in circulating [[estrogen]], a decrease in [[androgen]] or the sensitivity of the [[breast]] tissue to the circulating [[estrogen]].<ref name="pmid25905330">{{cite journal |vauthors=De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Swerdloff RS, Ng JCM |title= |journal= |volume= |issue= |pages= |year= |pmid=25905330 |doi= |url=}}</ref>
*The imbalance of estrogen/androgen can be due to increased levels of free estrogen secreted by the adrenals or testes, decreased estrogen breakdown, increased availability of estrogen precursors, exposure to estrogen like products or use of drugs that displaces more estrogen than androgen from sex hormone-binding globulin (SHBG). On the other hand, the imbalance can result from altered androgen metabolism, decreased androgen production, increased androgen binding (relative to estrogen) by SHBG, or androgen receptor defects.<ref name="pmid19880691">{{cite journal| author=Johnson RE, Murad MH| title=Gynecomastia: pathophysiology, evaluation, and management. | journal=Mayo Clin Proc | year= 2009 | volume= 84 | issue= 11 | pages= 1010-5 | pmid=19880691 | doi=10.1016/S0025-6196(11)60671-X | pmc=2770912 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19880691  }} </ref> <ref name="pmid11546925">{{cite journal| author=Mathur R, Braunstein GD| title=Gynecomastia: pathomechanisms and treatment strategies. | journal=Horm Res | year= 1997 | volume= 48 | issue= 3 | pages= 95-102 | pmid=11546925 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11546925  }} </ref> <ref name="pmid25905330">{{cite journal |vauthors=De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Swerdloff RS, Ng JCM |title= |journal= |volume= |issue= |pages= |year= |pmid=25905330 |doi= |url=}}</ref>
*The imbalance of [[estrogen]]/[[androgen]] can be due to increased levels of free [[estrogen]] secreted by the [[Adrenal|adrenals]] or [[testes]], decreased [[estrogen]] breakdown, increased availability of [[estrogen]] precursors, exposure to [[estrogen]] like products or use of drugs that displaces more [[estrogen]] than [[androgen]] from [[sex hormone-binding globulin]] [[Sex hormone binding globulin|(SHBG).]]
====Hormones involved in breast development====
*On the other hand, the imbalance can result from altered [[androgen]] metabolism, decreased [[androgen]] production, increased [[androgen]] binding (relative to [[estrogen]]) by [[SHBG]], or [[androgen]] receptor defects.<ref name="pmid19880691">{{cite journal| author=Johnson RE, Murad MH| title=Gynecomastia: pathophysiology, evaluation, and management. | journal=Mayo Clin Proc | year= 2009 | volume= 84 | issue= 11 | pages= 1010-5 | pmid=19880691 | doi=10.1016/S0025-6196(11)60671-X | pmc=2770912 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19880691  }} </ref> <ref name="pmid11546925">{{cite journal| author=Mathur R, Braunstein GD| title=Gynecomastia: pathomechanisms and treatment strategies. | journal=Horm Res | year= 1997 | volume= 48 | issue= 3 | pages= 95-102 | pmid=11546925 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11546925  }} </ref> <ref name="pmid25905330">{{cite journal |vauthors=De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Swerdloff RS, Ng JCM |title= |journal= |volume= |issue= |pages= |year= |pmid=25905330 |doi= |url=}}</ref>
*Estrogen and Progesterone act in a coordinated manner to support breast development. Estrogen helps duct growth and progesterone promotes alveolar development.<ref name="pmid10935020">{{cite journal |vauthors=Bocchinfuso WP, Korach KS |title=Mammary gland development and tumorigenesis in estrogen receptor knockout mice |journal=J Mammary Gland Biol Neoplasia |volume=2 |issue=4 |pages=323–34 |year=1997 |pmid=10935020 |doi= |url=}}</ref> <ref name="pmid8248223">{{cite journal |vauthors=Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O |title=Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue=23 |pages=11162–6 |year=1993 |pmid=8248223 |pmc=47942 |doi= |url=}}</ref>
[[image:Gynecomastia pathophysiology.jpeg|400px|center]]
*Growth hormone which acts through IGF-1 acts as a mediator in the presence of estrogen and progesterone for ductal breast duct development.<ref name="pmid10791764">{{cite journal |vauthors=Kleinberg DL, Feldman M, Ruan W |title=IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis |journal=J Mammary Gland Biol Neoplasia |volume=5 |issue=1 |pages=7–17 |year=2000 |pmid=10791764 |doi= |url=}}</ref> In a population based study of adolescent school boys, IGH-1 levels were higher in boys with pubertal gynecomastia suggesting the involvement of GH and IGF-1 in the pathogenesis of gynecomastia.<ref name="pmid24033660">{{cite journal |vauthors=Mieritz MG, Sorensen K, Aksglaede L, Mouritsen A, Hagen CP, Hilsted L, Andersson AM, Juul A |title=Elevated serum IGF-I, but unaltered sex steroid levels, in healthy boys with pubertal gynaecomastia |journal=Clin. Endocrinol. (Oxf) |volume=80 |issue=5 |pages=691–8 |year=2014 |pmid=24033660 |doi=10.1111/cen.12323 |url=}}</ref>
*Prolactin in the presence of estrogen and progesterone also supports breast development. It also plays an indirect role as it causes central hypogonadism which alters the androgen/estrogen balance.<ref name="pmid25905330">{{cite journal |vauthors=De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Swerdloff RS, Ng JCM |title= |journal= |volume= |issue= |pages= |year= |pmid=25905330 |doi= |url=}}</ref> <ref name="pmid22790552">{{cite journal| author=Barros AC, Sampaio Mde C| title=Gynecomastia: physiopathology, evaluation and treatment. | journal=Sao Paulo Med J | year= 2012 | volume= 130 | issue= 3 | pages= 187-97 | pmid=22790552 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22790552  }} </ref>
*Aromatase catalyzes the conversion of androgens to estrogen and so initiate the cascade to breast development. So, gynecomastia can result from overexpression of aromatase.<ref name="pmid12239119">{{cite journal| author=Li X, Wärri A, Mäkelä S, Ahonen T, Streng T, Santti R et al.| title=Mammary gland development in transgenic male mice expressing human P450 aromatase. | journal=Endocrinology | year= 2002 | volume= 143 | issue= 10 | pages= 4074-83 | pmid=12239119 | doi=10.1210/en.2002-220181 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12239119  }} </ref> <ref name="pmid12736278">{{cite journal| author=Shozu M, Sebastian S, Takayama K, Hsu WT, Schultz RA, Neely K et al.| title=Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene. | journal=N Engl J Med | year= 2003 | volume= 348 | issue= 19 | pages= 1855-65 | pmid=12736278 | doi=10.1056/NEJMoa021559 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12736278  }} </ref>


PIC...???
====Some examples regarding gynecomastia development based on the pathophysiology include: ====
{| class="wikitable"
!Conditions causing increased estrogen
!Conditions causing decreased testosterone
|-
|
* [[Liver disease|Chronic liver disease]]
|
* [[Androgen-insensitivity syndrome]]
|-
|
* [[Hyperthyroidism]]
|
* [[Five alpha-reductase deficiency]]
|-
|
* [[Extragonadal germ cell tumors]]
|
* [[Hypopituitarism]]
|-
|
* [[Large cell carcinoma of the lung]]
|
* [[Kallman Syndrome]]
|-
|
* [[Chronic kidney disease]]
|
* [[Klinefelter Syndrome]]
|-
|
|
* [[Testicular trauma]]
|}


==Genetics==
==Genetics==
*[Disease name] is transmitted in [mode of genetic transmission] pattern.
Genes involved in the pathogenesis of [[Aromatase|aromatase overexpression]] form of gynecomastia is encoded by a [[chromosome]] 15q21.2.<ref name="pmid12736278">{{cite journal| author=Shozu M, Sebastian S, Takayama K, Hsu WT, Schultz RA, Neely K et al.| title=Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene. | journal=N Engl J Med | year= 2003 | volume= 348 | issue= 19 | pages= 1855-65 | pmid=12736278 | doi=10.1056/NEJMoa021559 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12736278  }} </ref> As a result, any [[mutation]] in the mentioned loci result in [[Aromatase|aromatase overexpression]].
*Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
*The development of [disease name] is the result of multiple genetic mutations.
*Aromatase is encoded by a gene in chromosome 15q21.2, so its overexpression can lead to gynecomastia.<ref name="pmid12736278">{{cite journal| author=Shozu M, Sebastian S, Takayama K, Hsu WT, Schultz RA, Neely K et al.| title=Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene. | journal=N Engl J Med | year= 2003 | volume= 348 | issue= 19 | pages= 1855-65 | pmid=12736278 | doi=10.1056/NEJMoa021559 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12736278  }} </ref>
 
==Associated Conditions==
==Associated Conditions==
 
Gynecomastia is associated with [[psychological]] [[stress]] such as:<ref name="WassersugOliffe2009">{{cite journal|last1=Wassersug|first1=Richard J.|last2=Oliffe|first2=John L.|title=The Social Context for Psychological Distress from Iatrogenic Gynecomastia with Suggestions for Its Management|journal=The Journal of Sexual Medicine|volume=6|issue=4|year=2009|pages=989–1000|issn=17436095|doi=10.1111/j.1743-6109.2008.01053.x}}</ref><ref name="StrømsvikRåheim2010">{{cite journal|last1=Strømsvik|first1=Nina|last2=Råheim|first2=Målfrid|last3=Øyen|first3=Nina|last4=Engebretsen|first4=Lars Fredrik|last5=Gjengedal|first5=Eva|title=Stigmatization and Male Identity: Norwegian Males’ Experience after Identification as BRCA1/2 Mutation Carriers|journal=Journal of Genetic Counseling|volume=19|issue=4|year=2010|pages=360–370|issn=1059-7700|doi=10.1007/s10897-010-9293-1}}</ref><ref name="HackSawatzky2010">{{cite journal|last1=Hack|first1=Thomas F.|last2=Sawatzky|first2=Jo-Ann|last3=Pedersen|first3=Allison E.|title=The Sequelae of Anxiety in Breast Cancer: A Human Response to Illness Model|journal=Oncology Nursing Forum|volume=37|issue=4|year=2010|pages=469–475|issn=0190-535X|doi=10.1188/10.ONF.469-475}}</ref><ref name="Senín-CalderónRodríguez-Testal2017">{{cite journal|last1=Senín-Calderón|first1=Cristina|last2=Rodríguez-Testal|first2=Juan F.|last3=Perona-Garcelán|first3=Salvador|last4=Perpiñá|first4=Conxa|title=Body image and adolescence: A behavioral impairment model|journal=Psychiatry Research|volume=248|year=2017|pages=121–126|issn=01651781|doi=10.1016/j.psychres.2016.12.003}}</ref>
*[[Depression]]
*Decreased [[self-esteem]]
*Body dissatisfaction
==Gross Pathology==
==Gross Pathology==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
On gross [[pathology]], characteristic findings of gynecomastia include:
*Excessive [[breast tissue]] and [[Areolar tissue|subareolar]] mass 
*Well circumscribed borders
*Firm surfaces


==Microscopic Pathology==
==Microscopic Pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
On microscopic inspection, gynecomastia histology shows:<ref name="pmid5539033">{{cite journal| author=Nicolis GL, Modlinger RS, Gabrilove JL| title=A study of the histopathology of human gynecomastia. | journal=J Clin Endocrinol Metab | year= 1971 | volume= 32 | issue= 2 | pages= 173-8 | pmid=5539033 | doi=10.1210/jcem-32-2-173 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5539033  }} </ref>
 
*[[Hyperplasia|Ductal hyperplasia]]
 
*Lengthening of the [[ducts]]
The condition can occur physiologically in [[neonate]]s, in adolescents,adults and in the elderly. In adolescent boys the condition is a source of distress, but for the large majority of boys whose pubertal gynecomastia is not due to [[obesity]], the breast development shrinks or disappears within a couple of years <ref>[http://www.keepkidshealthy.com/adolescent/adolescentproblems/gynecomastia.html Adolescent gynecomastia]</ref>. The common type of gynecomastia in males undergoing pueberty is idiopathic in nature.One should be aware that several causes of gynecomastia have significant sequela and need to be ruled out ethier by history and or laboratory examinations prior to treatment of the disorder. The most common presentation of gynecomastia is idiopathic in nature. It is important to note that pituitary and adrenal tumors can result in gynecomastia. In addition several other endocrinological disorders such as klinefelters syndrome can be associated with gynecomastia and should be ruled out in pre pubertal individuals.Male breast cancer although rare needs to be considered in the differential diagnosis, particularly in cases that are of rapid onset and  are  unilateral in nature. Several types of exogenously injested substances , most notably steroids, can result in gynecomastia. Breast prominence can result from [[Organ hypertrophy|hypertrophy]] of breast tissue, chest [[adipose tissue]] and skin, and is typically in combination. Two types of tissue : glandular ,breast tissue , and fat ,adipose cells,compose the tissue in the breast. Optimal treatment needs to be directed at correction of the glandular and fatty tissue along with the skin envelope in each patient. As the relative volumes of the aforementioned components of the breast differ from individual to individual a patient specific treament plan needs to be established in all cases.The treatment plan in addition to correction of the obvious physical manifestations of the disease may need to be combined with an appropriate medical workup to establish and if necessary treat any concomitant disorder. <ref>{{cite journal| last=Braunstein| first=GD| title=Gynecomastia| journal=N Engl J Med| year=1993| month=Feb 18| volume=328| issue=7| pages=490-5| id=PMID 8421478}}</ref> ''<ref>{{cite web
*[[inflammation]] surrounding the ducts
  | last = Allee
*Increase in periductal [[connective tissue]]
  | first = Mark R
  | title = Gynecomastia
  | publisher =  WebMD, Inc. (emedicine.com)
  | date = 2006-11-15
  | url = http://www.emedicine.com/med/topic934.htm
  | accessdate = 2007-05-20 }}</ref>.''
 
Physiologic gynecomastia occurs in neonates, at or before [[puberty]] and with [[Senescence|aging]]. Many cases of gynecomastia are [[idiopathic]], meaning they have no clear cause.
Potential pathologic causes of gynecomastia are: medications including hormones, increased serum [[estrogen]], decreased [[testosterone]] production, [[androgen]] receptor defects, chronic kidney disease, chronic liver disease, [[HIV]],<ref>{{cite journal| last=Peyriere| first=H| coauthors=et al| title=Report of gynecomastia in five male patients during antiretroviral therapy for HIV infection| journal=AIDS| year=1999| month=Oct 22| volume=13| issue=15| pages=2167-9| id=PMID 10546872}}</ref> and other chronic illness. Gynecomastia as a result of spinal cord injury and refeeding after starvation has been reported.<ref>{{cite journal| last=Heruti| first=RJ| coauthors=et al| title=Gynecomastia following spinal cord disorder|journal=Arch Phys Med Rehabil| year=1997| month=May |volume=78| issue=5| pages=534-7| id=PMID 9161376}}</ref> In 25% of cases, the cause of the gynecomastia is not known.
 
Medications cause 10-20% of cases of gynecomastia in post-adolescent adults. These include [[cimetidine]], [[omeprazole]], [[spironolactone]], [[imatinib|imatinib mesylate]], [[finasteride]] and certain [[antipsychotic]]s. Some act directly on the breast tissue, while others lead to increased secretion of [[prolactin]] from the [[pituitary]] by blocking the actions of [[dopamine]] (prolactin-inhibiting factor/PIF) on the [[lactotrope]] cell groups in the [[anterior pituitary]]. [[Androstenedione]], used as a performance enhancing food supplement, can lead to breast enlargement by excess [[estrogen]] activity.  Medications used in the treatment of [[prostate cancer]], such as [[antiandrogens]] and [[Gonadotropin-releasing hormone analog|GnRH analogs]] can also cause gynecomastia. [[Marijuana]] use is also thought by some to be a possible cause; however, published data is contradictory.<ref>{{cite journal |author=Thompson D, Carter J |title=Drug-induced gynecomastia |journal=Pharmacotherapy |volume=13 |issue=1 |pages=37-45 |year= |id=PMID 8094898}}</ref>
 
Increased estrogen levels can also occur in certain testicular [[tumors]], and in [[hyperthyroidism]]. Certain adrenal tumors cause elevated levels of [[androstenedione]] which is converted by the [[enzyme]] [[aromatase]] into [[estrone]], a form of estrogen. Other tumors that secrete [[hCG]] can increase estrogen. A decrease in estrogen clearance can occur in liver disease, and this may be the mechanism of gynecomastia in liver [[cirrhosis]]. [[Obesity]] tends to increase estrogen levels.<ref>{{cite journal| last=Glass |first=AR| title=Gynecomastia| journal=Endocrinol Metab Clin North Am| year=1994| month=Dec| volume=23| issue=4| pages=825-37| id=PMID 7705322}}</ref><ref>{{cite journal| last=Braunstein| first=GD| title=Aromatase and Gynecomastia| journal=Endocr Relat Cancer| year=1999| month= Jun| volume=6| issue=2| pages=315-24| id=PMID 10731125}}</ref>


Decreased [[testosterone]] production can occur in congenital or acquired testicular failure, for example in [[genetic disorder]]s such as [[Klinefelter Syndrome]]. Diseases of the [[hypothalamus]] or [[pituitary]] can also lead to low testosterone. Abuse of anabolic androgenic steroids (AAS) has a similar effect. Mutations to androgen receptors, such as those found in [[Kennedy disease]] can also cause gynecomastia.
[[Image:Gynecomastia 2 (2).jpg|200px|left|frame|'''Ductal hyperplasia''', source:https://librepathology.org]]
<br style="clear:left">


Although stopping these medications can lead to regression of the gynecomastia, surgery is sometimes necessary to eliminate the condition.
[[Image:1200px-Gynecomastoid hyperplasia - very high mag.jpg|thumb|400px|left|frame|'''Gynecomastoid hyperplasia''', source:https://librepathology.org]]
 
<br style="clear:left">
Repeated topical application of products containing [[Lavender oil|lavender]] and [[tea tree oil]]s among other unidentified ingredients to three prepubescent males coincided with gynecomastia; it has been theorised that this could be due to their estrogenic and antiandrogenic activity. However, other circumstances around the study are not clear, and the sample size was insignificant so serious scientific conclusions cannot be drawn.<ref>{{cite journal |author=Henley D, Lipson N, Korach K, Bloch C |title=Prepubertal gynecomastia linked to lavender and tea tree oils |journal=N Engl J Med |volume=356 |issue=5 |pages=479-85 |year=2007 |id=PMID 17267908}}</ref>


==References==
==References==
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[[Category:Disease]]
[[Category:Endocrinology]]

Latest revision as of 14:51, 15 November 2017

Gynecomastia Microchapters

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

Overview

The main pathophysiology behind gynecomastia is increased estrogen to androgen ratio which can occur through multiple mechanisms. These mechanisms can be physiological, pathological or pharmacological.

Pathophysiology

Hormones involved in breast development


 
 
 
 
 
 
 
 
 
 
Breast Tissue
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stimulatory Action
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhibitory Action
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estrogen
 
 
 
 
 
 
 
 
 
 
 
 
 
Androgens
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GH & IGF-1
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Pathogenesis

Some examples regarding gynecomastia development based on the pathophysiology include:

Conditions causing increased estrogen Conditions causing decreased testosterone

Genetics

Genes involved in the pathogenesis of aromatase overexpression form of gynecomastia is encoded by a chromosome 15q21.2.[8] As a result, any mutation in the mentioned loci result in aromatase overexpression.

Associated Conditions

Gynecomastia is associated with psychological stress such as:[11][12][13][14]

Gross Pathology

On gross pathology, characteristic findings of gynecomastia include:

Microscopic Pathology

On microscopic inspection, gynecomastia histology shows:[15]

Ductal hyperplasia, source:https://librepathology.org


Gynecomastoid hyperplasia, source:https://librepathology.org


References

  1. ↑ Bocchinfuso WP, Korach KS (1997). "Mammary gland development and tumorigenesis in estrogen receptor knockout mice". J Mammary Gland Biol Neoplasia. 2 (4): 323–34. PMID 10935020.
  2. ↑ Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O (1993). "Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene". Proc. Natl. Acad. Sci. U.S.A. 90 (23): 11162–6. PMC 47942. PMID 8248223.
  3. ↑ Kleinberg DL, Feldman M, Ruan W (2000). "IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis". J Mammary Gland Biol Neoplasia. 5 (1): 7–17. PMID 10791764.
  4. ↑ Mieritz MG, Sorensen K, Aksglaede L, Mouritsen A, Hagen CP, Hilsted L, Andersson AM, Juul A (2014). "Elevated serum IGF-I, but unaltered sex steroid levels, in healthy boys with pubertal gynaecomastia". Clin. Endocrinol. (Oxf). 80 (5): 691–8. doi:10.1111/cen.12323. PMID 24033660.
  5. ↑ 5.0 5.1 5.2 De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Swerdloff RS, Ng J. PMID 25905330. Vancouver style error: initials (help); Missing or empty |title= (help)
  6. ↑ Barros AC, Sampaio Mde C (2012). "Gynecomastia: physiopathology, evaluation and treatment". Sao Paulo Med J. 130 (3): 187–97. PMID 22790552.
  7. ↑ Li X, Wärri A, Mäkelä S, Ahonen T, Streng T, Santti R; et al. (2002). "Mammary gland development in transgenic male mice expressing human P450 aromatase". Endocrinology. 143 (10): 4074–83. doi:10.1210/en.2002-220181. PMID 12239119.
  8. ↑ 8.0 8.1 Shozu M, Sebastian S, Takayama K, Hsu WT, Schultz RA, Neely K; et al. (2003). "Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene". N Engl J Med. 348 (19): 1855–65. doi:10.1056/NEJMoa021559. PMID 12736278.
  9. ↑ Johnson RE, Murad MH (2009). "Gynecomastia: pathophysiology, evaluation, and management". Mayo Clin Proc. 84 (11): 1010–5. doi:10.1016/S0025-6196(11)60671-X. PMC 2770912. PMID 19880691.
  10. ↑ Mathur R, Braunstein GD (1997). "Gynecomastia: pathomechanisms and treatment strategies". Horm Res. 48 (3): 95–102. PMID 11546925.
  11. ↑ Wassersug, Richard J.; Oliffe, John L. (2009). "The Social Context for Psychological Distress from Iatrogenic Gynecomastia with Suggestions for Its Management". The Journal of Sexual Medicine. 6 (4): 989–1000. doi:10.1111/j.1743-6109.2008.01053.x. ISSN 1743-6095.
  12. ↑ Strømsvik, Nina; Råheim, Målfrid; Øyen, Nina; Engebretsen, Lars Fredrik; Gjengedal, Eva (2010). "Stigmatization and Male Identity: Norwegian Males' Experience after Identification as BRCA1/2 Mutation Carriers". Journal of Genetic Counseling. 19 (4): 360–370. doi:10.1007/s10897-010-9293-1. ISSN 1059-7700.
  13. ↑ Hack, Thomas F.; Sawatzky, Jo-Ann; Pedersen, Allison E. (2010). "The Sequelae of Anxiety in Breast Cancer: A Human Response to Illness Model". Oncology Nursing Forum. 37 (4): 469–475. doi:10.1188/10.ONF.469-475. ISSN 0190-535X.
  14. ↑ Senín-Calderón, Cristina; Rodríguez-Testal, Juan F.; Perona-Garcelán, Salvador; Perpiñá, Conxa (2017). "Body image and adolescence: A behavioral impairment model". Psychiatry Research. 248: 121–126. doi:10.1016/j.psychres.2016.12.003. ISSN 0165-1781.
  15. ↑ Nicolis GL, Modlinger RS, Gabrilove JL (1971). "A study of the histopathology of human gynecomastia". J Clin Endocrinol Metab. 32 (2): 173–8. doi:10.1210/jcem-32-2-173. PMID 5539033.
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