Amenorrhea differential diagnosis: Difference between revisions

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__NOTOC__
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{{Amenorrhea}}
[[Image:Home_logo1.png|right|250px|link=https://www.wikidoc.org/index.php/Amenorrhea]]
{{CMG}}; {{AE}} {{EG}}, {{MJ}}


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== Overview ==
As amenorrhea manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. Primary amenorrhea must be differentiated from other diseases that cause lack of [[menstrual cycle]], such as [[Mullerian agenesis]], [[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|3-beta-hydroxysteroid dehydrogenase type 2 deficiency]], [[androgen insensitivity syndrome]], [[Kallmann syndrome]], [[Turner syndrome]], and [[17-alpha-hydroxylase deficiency]]. In contrast, secondary amenorrhea must be differentiated from other diseases that cause [[menstrual cycle]] arrest, such as [[Primary ovarian failure|primary ovarian insufficiency]], [[hypothyroidism]], [[hyperprolactinemia]], [[polycystic ovary syndrome]], and [[Asherman's syndrome]].
 
== Differentiating Diseases with Amenorrhea from each other==
As amenorrhea manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. Primary amenorrhea must be differentiated from other diseases that cause lack of [[menstrual cycle]], such as [[Mullerian agenesis]], [[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|3-beta-hydroxysteroid dehydrogenase type 2 deficiency]], [[androgen insensitivity syndrome]], [[Kallmann syndrome]], [[Turner syndrome]], and [[17-alpha-hydroxylase deficiency]]. In contrast, secondary amenorrhea must be differentiated from other diseases that cause [[menstrual cycle]] arrest, such as [[Primary ovarian failure|primary ovarian insufficiency]], [[hypothyroidism]], [[hyperprolactinemia]], [[polycystic ovary syndrome]], and [[Asherman's syndrome]].
<div style="width: 85%;">
<small>
{|
|- style="background: #4479BA; color: #FFFFFF; text-align: center;"
! rowspan="2" |Group
! rowspan="2" |Diseases
! colspan="10" |Laboratory Findings
! colspan="4" |Physical Examination
! rowspan="2" |Other Findings
|- style="background: #4479BA; color: #FFFFFF; text-align: center;"
!Estrogen
!Progesterone
!GnRH
!LH
!FSH
!Androgen
!TSH
!T4
!PRL
!Karyotype
!Externl genitalia
!Breast development
!Pubic hair
!Uterus
|-
| rowspan="6" style="background: #7d7d7d; color: #FFFFFF; padding: 5px; text-align: center;" |'''Primary amenorrhea'''
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Mullerian agenesis]]<ref name="pmid11023205">{{cite journal |vauthors=Folch M, Pigem I, Konje JC |title=Müllerian agenesis: etiology, diagnosis, and management |journal=Obstet Gynecol Surv |volume=55 |issue=10 |pages=644–9 |year=2000 |pmid=11023205 |doi= |url=}}</ref>'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |46 [[XX]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | -
| style="background: #F5F5F5; padding: 5px;" |
* [[Urinary tract malformation|Urinary tract defects]]
* Fused [[vertebrae]]
|-
! style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|3-beta-hydroxysteroid dehydrogenase type 2 deficiency]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |46 [[XX]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |[[Clitoromegaly]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" | -/+
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px;" |
* [[Hyponatremia]]
* [[Hypokalemia]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Androgen insensitivity syndrome]]<ref name="pmid15237040">{{cite journal |vauthors= |title=Current evaluation of amenorrhea |journal=Fertil. Steril. |volume=82 |issue=1 |pages=266–72 |year=2004 |pmid=15237040 |doi=10.1016/j.fertnstert.2004.02.098 |url=}}</ref>'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |46 [[XY]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | -
| style="background: #F5F5F5; padding: 5px;" |
* [[Undescended testes|Undescended testis]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Kallmann syndrome]]<ref name="pmid7641400">{{cite journal |vauthors=Albanese A, Stanhope R |title=Investigation of delayed puberty |journal=Clin. Endocrinol. (Oxf) |volume=43 |issue=1 |pages=105–10 |year=1995 |pmid=7641400 |doi= |url=}}</ref>'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |46 [[XX]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" | -
| style="background: #F5F5F5; padding: 5px; text-align: center;" | -
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px;" |
* [[Anosmia]]/[[Hyposmia]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Turner syndrome]]<ref name="pmid15371580">{{cite journal |vauthors=Sybert VP, McCauley E |title=Turner's syndrome |journal=N. Engl. J. Med. |volume=351 |issue=12 |pages=1227–38 |year=2004 |pmid=15371580 |doi=10.1056/NEJMra030360 |url=}}</ref>'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |[[Turner syndrome|45 XO]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +/-
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px;" |
* [[Webbed neck]]
* Cardiac defects
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[17-alpha-hydroxylase deficiency]]'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |46 [[XY]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |[[Infantilism]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" | -
| style="background: #F5F5F5; padding: 5px; text-align: center;" | -
| style="background: #F5F5F5; padding: 5px; text-align: center;" | -
| style="background: #F5F5F5; padding: 5px;" |
* [[Hypertension]]
|-
| rowspan="5" style="background: #7d7d7d; color: #FFFFFF; padding: 5px; text-align: center;" |'''Secondary amenorrhea'''
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Primary ovarian failure|Primary ovarian insufficiency]]<ref name="pmid19196677">{{cite journal |vauthors=Nelson LM |title=Clinical practice. Primary ovarian insufficiency |journal=N. Engl. J. Med. |volume=360 |issue=6 |pages=606–14 |year=2009 |pmid=19196677 |pmc=2762081 |doi=10.1056/NEJMcp0808697 |url=}}</ref>'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |46 [[XX]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px;" |
* [[Osteoporosis]]
* [[Ischemic heart disease]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Hypothyroidism]]<ref name="pmid14575026">{{cite journal |vauthors=Kalro BN |title=Impaired fertility caused by endocrine dysfunction in women |journal=Endocrinol. Metab. Clin. North Am. |volume=32 |issue=3 |pages=573–92 |year=2003 |pmid=14575026 |doi= |url=}}</ref>'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |46 [[XX]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px;" |
* [[Fatigue]]
* Decreased [[Deep tendon reflex|deep tendon reflexes (DTR)]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Hyperprolactinemia]]<ref name="pmid15024895">{{cite journal |vauthors=Pickett CA |title=Diagnosis and management of pituitary tumors: recent advances |journal=Prim. Care |volume=30 |issue=4 |pages=765–89 |year=2003 |pmid=15024895 |doi= |url=}}</ref>'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |46 [[XX]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px;" |
* [[Galactorrhea]]
* [[Headaches]]
* [[Visual impairment|Visual disturbances]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Polycystic ovary syndrome]]<ref name="pmid12434783">{{cite journal |vauthors= |title=ACOG practice bulletin clinical management guidelines for obstetrician-gynecologists. Number 40, November 2002 |journal=Obstet Gynecol |volume=100 |issue=5 Pt 1 |pages=1045–50 |year=2002 |pmid=12434783 |doi= |url=}}</ref>'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |↓↓
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |'''↑'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |46 [[XX]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px;" |
* [[Hirsutism]]
* [[Insulin resistance]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Asherman's syndrome]]<ref>{{cite book | last = Fritz | first = Marc | title = Clinical gynecologic endocrinology and infertility | publisher = Wolters Kluwer Health/Lippincott Williams & Wilkins | location = Philadelphia | year = 2011 | isbn = 978-0781779685 }}</ref>'''
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" |46 [[XX]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |Nl
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px; text-align: center;" | +
| style="background: #F5F5F5; padding: 5px;" |
* History of [[uterus]] [[surgery]]
* [[Uterus]] scarring
|}
</small>
</div>


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
{{WH}}
{{WS}}


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[[Category:Medicine]]
 
[[Category:Overview complete]]
[[Category:Disease]]
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[[Category:Gynecology]]
[[Category:Signs and symptoms]
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Latest revision as of 20:22, 29 July 2020

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2], Mehrian Jafarizade, M.D [3]

Overview

As amenorrhea manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. Primary amenorrhea must be differentiated from other diseases that cause lack of menstrual cycle, such as Mullerian agenesis, 3-beta-hydroxysteroid dehydrogenase type 2 deficiency, androgen insensitivity syndrome, Kallmann syndrome, Turner syndrome, and 17-alpha-hydroxylase deficiency. In contrast, secondary amenorrhea must be differentiated from other diseases that cause menstrual cycle arrest, such as primary ovarian insufficiency, hypothyroidism, hyperprolactinemia, polycystic ovary syndrome, and Asherman's syndrome.

Differentiating Diseases with Amenorrhea from each other

As amenorrhea manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. Primary amenorrhea must be differentiated from other diseases that cause lack of menstrual cycle, such as Mullerian agenesis, 3-beta-hydroxysteroid dehydrogenase type 2 deficiency, androgen insensitivity syndrome, Kallmann syndrome, Turner syndrome, and 17-alpha-hydroxylase deficiency. In contrast, secondary amenorrhea must be differentiated from other diseases that cause menstrual cycle arrest, such as primary ovarian insufficiency, hypothyroidism, hyperprolactinemia, polycystic ovary syndrome, and Asherman's syndrome.

Group Diseases Laboratory Findings Physical Examination Other Findings
Estrogen Progesterone GnRH LH FSH Androgen TSH T4 PRL Karyotype Externl genitalia Breast development Pubic hair Uterus
Primary amenorrhea Mullerian agenesis[1] Nl Nl Nl Nl Nl Nl Nl Nl Nl 46 XX Nl + + -
3-beta-hydroxysteroid dehydrogenase type 2 deficiency Nl Nl Nl Nl Nl Nl Nl Nl 46 XX Clitoromegaly -/+ + +
Androgen insensitivity syndrome[2] Nl Nl Nl ↑↑ Nl Nl Nl 46 XY Nl + + -
Kallmann syndrome[3] ↓↓ Nl Nl Nl 46 XX Nl - - +
Turner syndrome[4] ↓↓ Nl Nl Nl Nl 45 XO Nl +/- + +
17-alpha-hydroxylase deficiency Nl Nl Nl Nl 46 XY Infantilism - - -
Secondary amenorrhea Primary ovarian insufficiency[5] ↓↓ Nl Nl Nl Nl 46 XX Nl + + +
Hypothyroidism[6] Nl Nl Nl Nl Nl ↑↑ ↓↓ Nl 46 XX Nl + + +
Hyperprolactinemia[7] Nl Nl 46 XX Nl + + +
Polycystic ovary syndrome[8] ↓↓ ↓↓ Nl Nl Nl 46 XX Nl + + +
Asherman's syndrome[9] Nl Nl Nl Nl Nl Nl Nl Nl Nl 46 XX Nl + + +

References

  1. Folch M, Pigem I, Konje JC (2000). "Müllerian agenesis: etiology, diagnosis, and management". Obstet Gynecol Surv. 55 (10): 644–9. PMID 11023205.
  2. "Current evaluation of amenorrhea". Fertil. Steril. 82 (1): 266–72. 2004. doi:10.1016/j.fertnstert.2004.02.098. PMID 15237040.
  3. Albanese A, Stanhope R (1995). "Investigation of delayed puberty". Clin. Endocrinol. (Oxf). 43 (1): 105–10. PMID 7641400.
  4. Sybert VP, McCauley E (2004). "Turner's syndrome". N. Engl. J. Med. 351 (12): 1227–38. doi:10.1056/NEJMra030360. PMID 15371580.
  5. Nelson LM (2009). "Clinical practice. Primary ovarian insufficiency". N. Engl. J. Med. 360 (6): 606–14. doi:10.1056/NEJMcp0808697. PMC 2762081. PMID 19196677.
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