Amenorrhea medical therapy: Difference between revisions

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{{Amenorrhea}}
{{Amenorrhea}}


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{{CMG}}; {{AE}}{{EG}}
 
{{CMG}}


==Overview==
==Overview==
 
Pharmacologic medical therapy is recommended in patients of amenorrhea associated with [[hypothalamic]] causes, [[pituitary]] causes, [[ovarian]] insufficiency, and chronic anovulation. Hormone replacement therapy such as [[estrogen]] and [[progesterone]] are the mainstay of treatment in patients of amenorrhea.
 
==Medical Therapy==
==Medical Therapy==
*Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].
*Pharmacologic medical therapy is recommended among patients with [[hypothalamic]] causes, [[pituitary]] causes, [[ovarian]] insufficiency, and chronic [[anovulation]].
*Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
*Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].
*Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].
===Amenorrhea===
===Amenorrhea===
*'''1 - Hypothalamic causes'''
*'''1 Hypothalamic causes'''
**1.1.1 '''Adult'''
**1.1 '''Adult'''
***Preferred regimen (1): [[Alora]] 0.05, 0.075, and 0.1 mg [[transdermal]] daily, applied twice weekly
***Preferred regimen (1): [[Alora]] 0.05, 0.075, and 0.1 mg [[transdermal]] daily, applied twice weekly '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month
***Preferred regimen (2): [[Climara]] 0.025, 0.05, 0.075, and 0.1 mg [[transdermal]] daily, applied once weekly
***Preferred regimen (2): [[Climara]] 0.025, 0.05, 0.075, and 0.1 mg [[transdermal]] daily, applied once weekly '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month
***Preferred regimen (3): [[Esclim]] 0.025, 0.0375, 0.05, 0.075, 0.1 mg [[transdermal]] daily, applied twice weekly
***Preferred regimen (3): [[Esclim]] 0.025, 0.0375, 0.05, 0.075, 0.1 mg [[transdermal]] daily, applied twice weekly '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month
***Preferred regimen (4): [[Vivelledot|Vivelle-dot]] 0.037, 0.05, 0.075, 0.1 mg [[transdermal]] daily, applied twice weekly
***Preferred regimen (4): [[Vivelledot|Vivelle-dot]] 0.037, 0.05, 0.075, 0.1 mg [[transdermal]] daily, applied twice weekly '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month
***Preferred regimen (5): [[Premarin]] 0.625-1.25 mg PO daily
***Preferred regimen (5): [[Premarin]] 0.625-1.25 mg PO daily '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month
***Preferred regimen (6): [[Medroxyprogesterone acetate]] 10 mg PO for 12 days each month
*'''2 Pituitary causes'''
***Alternative regimen (1): [[drug name]] 500 mg PO q6h for 7–10 days
**2.1 '''Hyperprolactinemia'''
***Alternative regimen (2): [[drug name]] 500 mg PO q12h for 14–21 days
***2.1.1 '''Drug-induced hyperprolactinemia'''
***Alternative regimen (3): [[drug name]] 500 mg PO q6h for 14–21 days
****Preferred regimen (1): Micronized 17-β [[estradiol]] 1-2 mg PO daily '''''PLUS''''' [[medroxyprogesterone acetate]] 2.5-5.0 mg PO daily (continuous)
**1.1.2 '''Pediatric'''
****Preferred regimen (2): Micronized 17-β [[estradiol]] 1-2 mg PO daily '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month (sequential)
***Preferred regimen (1): [[drug name]] 50 mg/kg PO per day q8h (maximum, 500 mg per dose)
****Preferred regimen (3): 17-β [[estradiol]] 1-2 mg [[transdermal]] daily '''''PLUS''''' micronized [[progesterone]] 100 mg PO daily (continuous)
***Preferred regimen (2): [[drug name]] 30 mg/kg PO per day in 2 divided doses (maximum, 500 mg per dose)
****Preferred regimen (4): 17-β [[estradiol]] 1-2 mg [[transdermal]] daily '''''PLUS''''' micronized [[progesterone]] 200 mg PO for 12 days each month (sequential)
***Alternative regimen (1): [[drug name]]10 mg/kg PO q6h (maximum, 500 mg per day)
****Alternative regimen (1): [[Cabergoline]] 0.25 mg PO twice weekly
***Alternative regimen (2): [[drug name]] 7.5 mg/kg PO q12h (maximum, 500 mg per dose)
***2.1.2 '''Prolactinoma'''
***Alternative regimen (3): [[drug name]] 12.5 mg/kg PO q6h (maximum, 500 mg per dose)
****Preferred regimen (1): [[Cabergoline]] 0.25 mg PO twice weekly (can increase to 0.25 mg four times a week up to 1 mg twice weekly)
 
****Preferred regimen (2): [[Bromocriptine]] 1.25-2.5 mg PO daily initially (may increase by 2.5 mg/day every 2-7 days). Up to 30 mg PO daily
*'''2 - Pituitary causes'''
****Preferred regimen (3): [[Alora]] 0.05, 0.075, and 0.1 mg [[transdermal]] daily, applied twice weekly '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month
**1.1.1 '''Adult'''
****Preferred regimen (4): [[Climara]] 0.025, 0.05, 0.075, and 0.1 mg [[transdermal]] daily, applied once weekly '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month
***Preferred regimen (1): [[drug name]] 100 mg PO q12h for 10-21 days '''(Contraindications/specific instructions)'''
****Preferred regimen (5): [[Esclim]] 0.025, 0.0375, 0.05, 0.075, 0.1 mg [[transdermal]] daily, applied twice weekly '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month
***Preferred regimen (2): [[drug name]] 500 mg PO q8h for 14-21 days
****Preferred regimen (6): [[Vivelledot|Vivelle-dot]] 0.037, 0.05, 0.075, 0.1 mg [[transdermal]] daily, applied twice weekly '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month
***Preferred regimen (3): [[drug name]] 500 mg q12h for 14-21 days
****Preferred regimen (7): [[Premarin]] 0.625-1.25 mg PO daily '''''PLUS''''' [[medroxyprogesterone acetate]] 10 mg PO for 12 days each month
***Alternative regimen (1): [[drug name]] 500 mg PO q6h for 7–10 days
***2.1.3 '''Resistant and malignant prolactinoma'''
***Alternative regimen (2): [[drug name]] 500 mg PO q12h for 14–21 days
****Preferred regimen (1): [[Cabergoline]] 1 mg PO twice weekly
***Alternative regimen (3): [[drug name]] 500 mg PO q6h for 14–21 days
****Preferred regimen (2): [[Bromocriptine]] 30 mg PO daily
 
****Preferred regimen (3): [[Temozolomide]] 150–200 mg/m<sup>2</sup> IV infusion for five of every 28 days<ref name="pmid22584716">{{cite journal| author=Ortiz LD, Syro LV, Scheithauer BW, Rotondo F, Uribe H, Fadul CE et al.| title=Temozolomide in aggressive pituitary adenomas and carcinomas. | journal=Clinics (Sao Paulo) | year= 2012 | volume= 67 Suppl 1 | issue=  | pages= 119-23 | pmid=22584716 | doi= | pmc=3328813 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22584716  }} </ref>
** 1.1.2 '''Pediatric'''
***2.1.4 '''Prolactinoma during pregnancy'''
*** Preferred regimen (1): [[drug name]] 50 mg/kg PO per day q8h (maximum, 500 mg per dose)
****Preferred regimen (1): [[Bromocriptine]] 1.25-2.5 mg PO daily initially (may increase by 2.5 mg/day every 2-7 days). Up to 30 mg PO daily
*** Preferred regimen (2): [[drug name]] 30 mg/kg PO per day in 2 divided doses (maximum, 500 mg per dose)
* '''3 Ovary insufficiency'''
***Alternative regimen (1): [[drug name]]10 mg/kg PO q6h (maximum, 500 mg per day)
***Alternative regimen (2): [[drug name]] 7.5 mg/kg PO q12h (maximum, 500 mg per dose)
***Alternative regimen (3): [[drug name]] 12.5 mg/kg PO q6h (maximum, 500 mg per dose)
 
* '''3 - Ovary insufficiency'''
** 3.1 '''Premature ovarian insufficiency'''<ref name="pmid28426619">{{cite journal |vauthors= |title=Committee Opinion No. 698: Hormone Therapy in Primary Ovarian Insufficiency |journal=Obstet Gynecol |volume=129 |issue=5 |pages=e134–e141 |year=2017 |pmid=28426619 |doi=10.1097/AOG.0000000000002044 |url=}}</ref>
** 3.1 '''Premature ovarian insufficiency'''<ref name="pmid28426619">{{cite journal |vauthors= |title=Committee Opinion No. 698: Hormone Therapy in Primary Ovarian Insufficiency |journal=Obstet Gynecol |volume=129 |issue=5 |pages=e134–e141 |year=2017 |pmid=28426619 |doi=10.1097/AOG.0000000000002044 |url=}}</ref>
*** 3.1.1 '''Adult'''
*** 3.1.1 '''Adult'''
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****Preferred regimen (2): Micronized [[progesterone]] 200 mg PO daily on the 100th–120th days of 3-month cycle 
****Preferred regimen (2): Micronized [[progesterone]] 200 mg PO daily on the 100th–120th days of 3-month cycle 


* '''4 - Chronic anovulation'''
* '''4 Chronic anovulation'''
** 4.1 '''Polycystic ovary syndrome (PCOS)'''
** 4.1 '''Polycystic ovary syndrome (PCOS)'''
*** 4.1.1 '''Adult'''
*** 4.1.1 '''Adult'''
Line 83: Line 72:
****Alternative regimen (3): [[Orlistat]] 120 mg PO q8h<ref name="pmid15536162">{{cite journal |vauthors=Jayagopal V, Kilpatrick ES, Holding S, Jennings PE, Atkin SL |title=Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome |journal=J. Clin. Endocrinol. Metab. |volume=90 |issue=2 |pages=729–33 |year=2005 |pmid=15536162 |doi=10.1210/jc.2004-0176 |url=}}</ref>
****Alternative regimen (3): [[Orlistat]] 120 mg PO q8h<ref name="pmid15536162">{{cite journal |vauthors=Jayagopal V, Kilpatrick ES, Holding S, Jennings PE, Atkin SL |title=Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome |journal=J. Clin. Endocrinol. Metab. |volume=90 |issue=2 |pages=729–33 |year=2005 |pmid=15536162 |doi=10.1210/jc.2004-0176 |url=}}</ref>
****Alternative regimen (4): [[Troglitazone]] 300-600 mg PO daily (weight gain)<ref name="pmid11297595">{{cite journal |vauthors=Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, O'Keefe M, Ghazzi MN |title=Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial |journal=J. Clin. Endocrinol. Metab. |volume=86 |issue=4 |pages=1626–32 |year=2001 |pmid=11297595 |doi=10.1210/jcem.86.4.7375 |url=}}</ref>
****Alternative regimen (4): [[Troglitazone]] 300-600 mg PO daily (weight gain)<ref name="pmid11297595">{{cite journal |vauthors=Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, O'Keefe M, Ghazzi MN |title=Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial |journal=J. Clin. Endocrinol. Metab. |volume=86 |issue=4 |pages=1626–32 |year=2001 |pmid=11297595 |doi=10.1210/jcem.86.4.7375 |url=}}</ref>
****Alternative regimen (5): [[Follicle stimulating hormone|Follicle stimulating hormone (FSH)]] 150 IU SC or IM daily [cause ovarian hyperstimulation syndrome (OHSS)<ref name="pmid6768596">{{cite journal |vauthors=Wang CF, Gemzell C |title=The use of human gonadotropins for the induction of ovulation in women with polycystic ovarian disease |journal=Fertil. Steril. |volume=33 |issue=5 |pages=479–86 |year=1980 |pmid=6768596 |doi= |url=}}</ref>]
****Alternative regimen (5): [[Follicle stimulating hormone|Follicle stimulating hormone (FSH)]] 150 IU SC or IM daily [cause ovarian hyperstimulation syndrome (OHSS)]<ref name="pmid6768596">{{cite journal |vauthors=Wang CF, Gemzell C |title=The use of human gonadotropins for the induction of ovulation in women with polycystic ovarian disease |journal=Fertil. Steril. |volume=33 |issue=5 |pages=479–86 |year=1980 |pmid=6768596 |doi= |url=}}</ref>
***4.1.2 '''Pediatric'''
***4.1.2 '''Pediatric'''
****Preferred regimen (1): [[Metformin]] 1.50–2.55 g PO per day<ref name="GlueckWang2001">{{cite journal|last1=Glueck|first1=C.J|last2=Wang|first2=Ping|last3=Fontaine|first3=Robert|last4=Tracy|first4=Trent|last5=Sieve-Smith|first5=Luann|title=Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS)11The full text of this article is available via JAH Online at http://www.elsevier.com/locate/jahonline.|journal=Journal of Adolescent Health|volume=29|issue=3|year=2001|pages=160–169|issn=1054139X|doi=10.1016/S1054-139X(01)00202-6}}</ref>  
****Preferred regimen (1): [[Metformin]] 1.50–2.55 g PO per day<ref name="GlueckWang2001">{{cite journal|last1=Glueck|first1=C.J|last2=Wang|first2=Ping|last3=Fontaine|first3=Robert|last4=Tracy|first4=Trent|last5=Sieve-Smith|first5=Luann|title=Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS)11The full text of this article is available via JAH Online|url= http://www.elsevier.com/locate/jahonline.|journal=Journal of Adolescent Health|volume=29|issue=3|year=2001|pages=160–169|issn=1054139X|doi=10.1016/S1054-139X(01)00202-6}}</ref>


===Lifestyle Changes===
===Oral contraceptive pills (OCPs)===
The best way to treat 'athletic' amenorrhoea is to decrease the amount and intensity of exercise. Weight gain may be helpful as well. To prevent osteoporosis, consider oral contraceptives. Pulsatile gonadotropin-releasing hormone (GnRH) or exogenous gonadotropins may be necessary.
*Different studies have shown that [[OCP]] therapy can slow down the [[bone loss]] process in patients with [[exercise]]- and [[anorexia]]-associated amenorrhea. The detailed results are as following table:<ref name="pmid18180975">{{cite journal |vauthors=Vescovi JD, Jamal SA, De Souza MJ |title=Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature |journal=Osteoporos Int |volume=19 |issue=4 |pages=465–78 |year=2008 |pmid=18180975 |doi=10.1007/s00198-007-0518-6 |url=}}</ref>
{|
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Type of amenorrhea
! colspan="2" style="background:#4479BA; color: #FFFFFF;" align="center" + |Medicine
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Dosage
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Treatment duration
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Bone mineral density (BMD) site
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Outcome
|-
! rowspan="21" style="background:#7d7d7d; color: #FFFFFF;" align="center" + |Exercise-associated<br>functional amenorrhea
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.035 mg
| rowspan="2" style="background:#F5F5F5;" align="center" + |12 months
| rowspan="2" style="background:#F5F5F5;" + |[[Lumbar spine]] and [[femoral neck]]
| rowspan="2" style="background:#F5F5F5;" + |Increased [[Bone mineral density|BMD]] in all sites<ref name="pmid9166162">{{cite journal |vauthors=Hergenroeder AC, Smith EO, Shypailo R, Jones LA, Klish WJ, Ellis K |title=Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months |journal=Am. J. Obstet. Gynecol. |volume=176 |issue=5 |pages=1017–25 |year=1997 |pmid=9166162 |doi= |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Norethindrone]]<br>[[Medroxyprogesterone]]
| style="background:#F5F5F5;" align="center" + |0.5-1.0 mg<br>10 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.03 or 0.02 mg
| rowspan="2" style="background:#F5F5F5;" align="center" + |12 months
| rowspan="2" style="background:#F5F5F5;" + |[[Lumbar spine]]
| rowspan="2" style="background:#F5F5F5;" + |Increased [[Bone mineral density|BMD]] in all sites<ref name="pmid11725730">{{cite journal |vauthors=Castelo-Branco C, Vicente JJ, Pons F, Martínez de Osaba MJ, Casals E, Vanrell JA |title=Bone mineral density in young, hypothalamic oligoamenorrheic women treated with oral contraceptives |journal=J Reprod Med |volume=46 |issue=10 |pages=875–9 |year=2001 |pmid=11725730 |doi= |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Desogestrel]]
| style="background:#F5F5F5;" align="center" + |0.15 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.030 mg
| rowspan="2" style="background:#F5F5F5;" align="center" + |10 months
| rowspan="2" style="background:#F5F5F5;" + |[[Lumbar spine]] and legs
| rowspan="2" style="background:#F5F5F5;" + |Increase [[Bone mineral density|BMD]] in [[lumbar spine]] not in legs<ref name="pmid15328063">{{cite journal |vauthors=Rickenlund A, Carlström K, Ekblom B, Brismar TB, Von Schoultz B, Hirschberg AL |title=Effects of oral contraceptives on body composition and physical performance in female athletes |journal=J. Clin. Endocrinol. Metab. |volume=89 |issue=9 |pages=4364–70 |year=2004 |pmid=15328063 |doi=10.1210/jc.2003-031334 |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Levonorgestrel]]
| style="background:#F5F5F5;" align="center" + |0.150 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.05 mg
| rowspan="2" style="background:#F5F5F5;" align="center" + |8 months
| rowspan="2" style="background:#F5F5F5;" + |[[Lumbar spine]] and [[radius]]
| rowspan="2" style="background:#F5F5F5;" + |Increase [[Bone mineral density|BMD]] in [[lumbar spine]] not in [[radius]]<ref name="pmid2970444">{{cite journal |vauthors=De Crée C, Lewin R, Ostyn M |title=Suitability of cyproterone acetate in the treatment of osteoporosis associated with athletic amenorrhea |journal=Int J Sports Med |volume=9 |issue=3 |pages=187–92 |year=1988 |pmid=2970444 |doi= |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Cyproterone acetate]]
| style="background:#F5F5F5;" align="center" + |2 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |Conjugated [[estrogen]]
| style="background:#F5F5F5;" align="center" + |0.0625 mg
| rowspan="2" style="background:#F5F5F5;" align="center" + |24 months
| rowspan="2" style="background:#F5F5F5;" + |[[Lumbar spine]] and [[femoral neck]]
| rowspan="2" style="background:#F5F5F5;" + |Increased [[Bone mineral density|BMD]] in all sites<ref name="pmid8885817">{{cite journal |vauthors=Cumming DC |title=Exercise-associated amenorrhea, low bone density, and estrogen replacement therapy |journal=Arch. Intern. Med. |volume=156 |issue=19 |pages=2193–5 |year=1996 |pmid=8885817 |doi= |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Transdermal]] [[estradiol]]
| style="background:#F5F5F5;" align="center" + |0.05 mg
|-
| rowspan="2" style="background:#DCDCDC;" align="center" + |12 days
| style="background:#DCDCDC;" align="center" + |[[Estriol]]
| style="background:#F5F5F5;" align="center" + |1 mg
| rowspan="7" style="background:#F5F5F5;" align="center" + |9.3 months
| rowspan="7" style="background:#F5F5F5;" + |[[Lumbar spine]], [[femoral neck]], and [[trochanter]]
| rowspan="7" style="background:#F5F5F5;" + |No change [[Bone mineral density|BMD]] in any sites<ref name="pmid10692976">{{cite journal |vauthors=Gibson JH, Mitchell A, Reeve J, Harries MG |title=Treatment of reduced bone mineral density in athletic amenorrhea: a pilot study |journal=Osteoporos Int |volume=10 |issue=4 |pages=284–9 |year=1999 |pmid=10692976 |doi=10.1007/s001980050228 |url=}}</ref>
|-
| style="background:#DCDCDC;" align="center" + |[[Estradiol]]
| style="background:#F5F5F5;" align="center" + |2 mg
|-
| rowspan="3" style="background:#DCDCDC;" align="center" + |10 days
| style="background:#DCDCDC;" align="center" + |[[Estriol]]
| style="background:#F5F5F5;" align="center" + |1 mg
|-
| style="background:#DCDCDC;" align="center" + |[[Estradiol]]
| style="background:#F5F5F5;" align="center" + |2 mg
|-
| style="background:#DCDCDC;" align="center" + |[[Norethisterone]]
| style="background:#F5F5F5;" align="center" + |1 mg
|-
| rowspan="2" style="background:#DCDCDC;" align="center" + |6 days
| style="background:#DCDCDC;" align="center" + |[[Estriol]]
| style="background:#F5F5F5;" align="center" + |0.5 mg
|-
| style="background:#DCDCDC;" align="center" + |[[Estradiol]]
| style="background:#F5F5F5;" align="center" + |1 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Premarin]]
| style="background:#F5F5F5;" align="center" + |0.625 mg
| rowspan="2" style="background:#F5F5F5;" align="center" + |24 months
| rowspan="2" style="background:#F5F5F5;" + |[[Lumbar spine]], [[wrist]], and [[foot]]
| rowspan="2" style="background:#F5F5F5;" + |Increase [[Bone mineral density|BMD]] in [[lumbar spine]], neither in [[wrist]] nor in [[foot]]<ref name="pmid12909505">{{cite journal |vauthors=Warren MP, Brooks-Gunn J, Fox RP, Holderness CC, Hyle EP, Hamilton WG, Hamilton L |title=Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: a longitudinal study |journal=Fertil. Steril. |volume=80 |issue=2 |pages=398–404 |year=2003 |pmid=12909505 |doi= |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Provera]]
| style="background:#F5F5F5;" align="center" + |10 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.035 mg
| rowspan="2" style="background:#F5F5F5;" align="center" + |10 months
| rowspan="2" style="background:#F5F5F5;" + |[[Lumbar spine]] and [[femoral neck]]
| rowspan="2" style="background:#F5F5F5;" + |Increase [[Bone mineral density|BMD]] in [[lumbar spine]] not in [[femoral neck]]<ref name="pmid16102557">{{cite journal |vauthors=Warren MP, Miller KK, Olson WH, Grinspoon SK, Friedman AJ |title=Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study |journal=Contraception |volume=72 |issue=3 |pages=206–11 |year=2005 |pmid=16102557 |doi=10.1016/j.contraception.2005.03.007 |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Norgestimate]]
| style="background:#F5F5F5;" align="center" + |0.180–0.250 mg
|-
! rowspan="16" style="background:#7d7d7d; color: #FFFFFF;" align="center" + |Anorexia-associated<br>functional amenorrhea
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.020–0.035 mg
| rowspan="2" style="background:#F5F5F5;" align="center" + |12 months
| rowspan="2" style="background:#F5F5F5;" + |[[Lumbar spine]] and [[femoral neck]]
| rowspan="2" style="background:#F5F5F5;" + |No change [[Bone mineral density|BMD]] in any sites<ref name="pmid12106749">{{cite journal |vauthors=Golden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, Shenker IR |title=The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa |journal=J Pediatr Adolesc Gynecol |volume=15 |issue=3 |pages=135–43 |year=2002 |pmid=12106749 |doi= |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Norgestimate]]<br>[[Norgestrel]]<br>[[Norethindrone acetate]]<br>[[Levonorgestrel]]
| style="background:#F5F5F5;" align="center" + |0.180–0.250 mg<br>0.5 mg<br>0.5-1.0 mg<br>-
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.05 mg
| rowspan="2" style="background:#F5F5F5;" align="center" + |12 months
| rowspan="2" style="background:#F5F5F5;" + |[[Lumbar spine]]
| rowspan="2" style="background:#F5F5F5;" + |No change [[Bone mineral density|BMD]]<ref name="pmid11751066">{{cite journal |vauthors=Muñoz MT, Morandé G, García-Centenera JA, Hervás F, Pozo J, Argente J |title=The effects of estrogen administration on bone mineral density in adolescents with anorexia nervosa |journal=Eur. J. Endocrinol. |volume=146 |issue=1 |pages=45–50 |year=2002 |pmid=11751066 |doi= |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Norgestrel]]
| style="background:#F5F5F5;" align="center" + |0.5 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Premarin]]
| style="background:#F5F5F5;" align="center" + |0.625 mg
| rowspan="3" style="background:#F5F5F5;" align="center" + |18 months
| rowspan="3" style="background:#F5F5F5;" + |[[Lumbar spine]]
| rowspan="3" style="background:#F5F5F5;" + |No change [[Bone mineral density|BMD]]<ref name="pmid7883849">{{cite journal |vauthors=Klibanski A, Biller BM, Schoenfeld DA, Herzog DB, Saxe VC |title=The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa |journal=J. Clin. Endocrinol. Metab. |volume=80 |issue=3 |pages=898–904 |year=1995 |pmid=7883849 |doi=10.1210/jcem.80.3.7883849 |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Provera]]
| style="background:#F5F5F5;" align="center" + |5 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.035 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Premarin]]
| style="background:#F5F5F5;" align="center" + |0.3–0.625 mg daily
| style="background:#F5F5F5;" align="center" + |4.3 years
| style="background:#F5F5F5;" + |[[Lumbar spine]] and [[femoral neck]]
| style="background:#F5F5F5;" + |Increased [[Bone mineral density|BMD]] in all sites<ref name="pmid10999805">{{cite journal |vauthors=Karlsson MK, Weigall SJ, Duan Y, Seeman E |title=Bone size and volumetric density in women with anorexia nervosa receiving estrogen replacement therapy and in women recovered from anorexia nervosa |journal=J. Clin. Endocrinol. Metab. |volume=85 |issue=9 |pages=3177–82 |year=2000 |pmid=10999805 |doi=10.1210/jcem.85.9.6796 |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.020 mg
| rowspan="3" style="background:#F5F5F5;" align="center" + |12 months
| rowspan="3" style="background:#F5F5F5;" + |[[Lumbar spine]] and [[femoral neck]]
| rowspan="3" style="background:#F5F5F5;" + |No change [[Bone mineral density|BMD]] in any sites<ref name="pmid12414853">{{cite journal |vauthors=Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS |title=Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=11 |pages=4935–41 |year=2002 |pmid=12414853 |doi=10.1210/jc.2002-020545 |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Levonorgestrel]]
| style="background:#F5F5F5;" align="center" + |0.1 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[DHEA|Dihydroepiandrostendion (DHEA)]]
| style="background:#F5F5F5;" align="center" + |50 mg daily
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Recombinant]] [[Insulin-like growth factor 1|IGF-1]]
| style="background:#F5F5F5;" align="center" + |30 mg/kg twice daily
| rowspan="3" style="background:#F5F5F5;" align="center" + |9 months
| rowspan="3" style="background:#F5F5F5;" + |[[Lumbar spine]], [[femoral neck]], and [[radius]]
| rowspan="3" style="background:#F5F5F5;" + |No change [[Bone mineral density|BMD]] in any sites<ref name="pmid12050268">{{cite journal |vauthors=Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A |title=Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue=6 |pages=2883–91 |year=2002 |pmid=12050268 |doi=10.1210/jcem.87.6.8574 |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.035 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Norethindrone]]
| style="background:#F5F5F5;" align="center" + |0.4 mg
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Ethinyl estradiol]]
| style="background:#F5F5F5;" align="center" + |0.035 mg
| rowspan="2" style="background:#F5F5F5;" align="center" + |13 cycles
| rowspan="2" style="background:#F5F5F5;" + |[[Lumbar spine]] and [[femoral neck]]
| rowspan="2" style="background:#F5F5F5;" + |No significant change [[Bone mineral density|BMD]] in any sites<ref name="pmid17116511">{{cite journal |vauthors=Strokosch GR, Friedman AJ, Wu SC, Kamin M |title=Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study |journal=J Adolesc Health |volume=39 |issue=6 |pages=819–27 |year=2006 |pmid=17116511 |doi=10.1016/j.jadohealth.2006.09.010 |url=}}</ref>
|-
| colspan="2" style="background:#DCDCDC;" align="center" + |[[Norgestimate]]
| style="background:#F5F5F5;" align="center" + |0.180–0.250 mg
|}


===Pharmacotherapy===
===Androgen therapy===
Hormone replacement therapy should be considered for ovarian failure. Unless receiving eggs from an [[egg donor]] or invitro fertilization, a woman is unable to conceive while she is amenorrhoeic. On the other hand, 'athletic' and drug-induced amenorrhoea has no effect on long term fertility as long as menstruation can recommence.   Similarly, to treat drug-induced amenorrhea, stopping the medication on the advice of a doctor is the usual course of action.
*Recent studies have shown that androgen therapy in the dose of 50, 100, or 200 mg of micronized [[DHEA]] daily may increase [[Bone mineral density|bone mineral density (BMD)]], and prevent osteoporotic [[fracture]]. However, there is no established long term study to prove this effect.<ref name="pmid12414853" />
 
===Recombinant insulin like growth factor 1 (IGF-1)===
In [[polycystic ovarian disease]] the following may be helpful:
*[[Recombinant]] [[Insulin-like growth factor-1|insulin like growth factor 1 (IGF-1)]] (30 μg/kg−1 twice per day) along with OCP (0.035 mg [[ethinyl estradiol]] and 0.4 mg [[norethindrone]]) prevents [[fracture]] in [[hypothalamic]] amenorrhea (due to [[anorexia nervosa]]) by increasing [[Bone mineral density|bone mineral density (BMD)]].<ref name="pmid12050268" />
* To decrease peripheral [[estrogen]], reduce weight
===Recombinant leptin===
* To decrease ovarian [[androgen]] secretion, consider [[oral contraceptive]]s
*Recent studies have shown that administering [[recombinant]] [[leptin]] (0.08 mg/kg) [[subcutaneous]] daily for 2–3 months can lead to an increase in [[bone]] formation markers; and also decrease [[fracture]] risk through [[secondary prevention]].<ref name="pmid15342807">{{cite journal |vauthors=Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS |title=Recombinant human leptin in women with hypothalamic amenorrhea |journal=N. Engl. J. Med. |volume=351 |issue=10 |pages=987–97 |year=2004 |pmid=15342807 |doi=10.1056/NEJMoa040388 |url=}}</ref>
* [[Clomiphene]] enhances fertility
===Bisphosphonates===
* [[Endometrial hyperplasia]] is prevented by cyclic [[progesterone]]
*In [[adolescent]] women with [[anorexia]]-induced amenorrhea, [[alendronate]] (10 mg) with [[calcium]] (1200 mg) and [[vitamin D]] (400 IU) for a year has been associated with significant improvement in [[bone loss]]. Therefore, [[Bisphosphonate|bisphosphonates]] can be used as [[secondary prevention]].<ref name="pmid15784715">{{cite journal |vauthors=Golden NH, Iglesias EA, Jacobson MS, Carey D, Meyer W, Schebendach J, Hertz S, Shenker IR |title=Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial |journal=J. Clin. Endocrinol. Metab. |volume=90 |issue=6 |pages=3179–85 |year=2005 |pmid=15784715 |doi=10.1210/jc.2004-1659 |url=}}</ref>
 
*Doses of [[bisphosphonates]] for [[secondary prevention]] of functional amenorrhea are as follows:
===Psychological Counseling===
{|
Psychological counseling may be helpful if there is the presence of a Y chromosome or absent mullerian organs.
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Medicine
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Dose
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Treatment duration
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Bone mineral density (BMD) site
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Outcome
|-
| style="background:#DCDCDC;" align="center" + |[[Etidronate]]
| style="background:#F5F5F5;" align="center" + |200 mg daily
| rowspan="3" style="background:#F5F5F5;" align="center" + |3 months
| rowspan="3" style="background:#F5F5F5;" + |[[Tibial]] midshaft
| rowspan="3" style="background:#F5F5F5;" + |Non-significant increase in [[Bone mineral density|BMD]] in all sites<ref name="pmid16231362">{{cite journal |vauthors=Nakahara T, Nagai N, Tanaka M, Muranaga T, Kojima S, Nozoe S, Naruo T |title=The effects of bone therapy on tibial bone loss in young women with anorexia nervosa |journal=Int J Eat Disord |volume=39 |issue=1 |pages=20–6 |year=2006 |pmid=16231362 |doi=10.1002/eat.20197 |url=}}</ref>
|-
| style="background:#DCDCDC;" align="center" + |[[Calcium]]
| style="background:#F5F5F5;" align="center" + |600 mg daily
|-
| style="background:#DCDCDC;" align="center" + |[[Vitamin D]]
| style="background:#F5F5F5;" align="center" + |1 μg daily
|-
| style="background:#DCDCDC;" align="center" + |[[Risedronate]]
| style="background:#F5F5F5;" align="center" + |5 mg
| rowspan="3" style="background:#F5F5F5;" align="center" + |9 months
| rowspan="3" style="background:#F5F5F5;" + |[[Lumbar spine]] and [[femoral neck]]
| rowspan="3" style="background:#F5F5F5;" + |Increase [[Bone mineral density|BMD]] in [[lumbar spine]] not in [[femoral neck]]<ref name="pmid15292325">{{cite journal |vauthors=Miller KK, Grieco KA, Mulder J, Grinspoon S, Mickley D, Yehezkel R, Herzog DB, Klibanski A |title=Effects of risedronate on bone density in anorexia nervosa |journal=J. Clin. Endocrinol. Metab. |volume=89 |issue=8 |pages=3903–6 |year=2004 |pmid=15292325 |doi=10.1210/jc.2003-031885 |url=}}</ref>
|-
| style="background:#DCDCDC;" align="center" + |[[Calcium]]
| style="background:#F5F5F5;" align="center" + |1500 mg
|-
| style="background:#DCDCDC;" align="center" + |[[Vitamin D]]
| style="background:#F5F5F5;" align="center" + |400 IU
|-
| style="background:#DCDCDC;" align="center" + |[[Alendronate]]
| style="background:#F5F5F5;" align="center" + |10 mg
| rowspan="3" style="background:#F5F5F5;" align="center" + |12 months
| rowspan="3" style="background:#F5F5F5;" + |[[Lumbar spine]] and [[femoral neck]]
| rowspan="3" style="background:#F5F5F5;" + |Non-significant increase in [[Bone mineral density|BMD]] in all sites<ref name="pmid15784715" />
|-
| style="background:#DCDCDC;" align="center" + |[[Calcium]]
| style="background:#F5F5F5;" align="center" + |1200 mg
|-
| style="background:#DCDCDC;" align="center" + |[[Vitamin D]]
| style="background:#F5F5F5;" align="center" + |400 IU
|}


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


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Latest revision as of 20:22, 29 July 2020

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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

Pharmacologic medical therapy is recommended in patients of amenorrhea associated with hypothalamic causes, pituitary causes, ovarian insufficiency, and chronic anovulation. Hormone replacement therapy such as estrogen and progesterone are the mainstay of treatment in patients of amenorrhea.

Medical Therapy

Amenorrhea

  • 1 Hypothalamic causes
  • 2 Pituitary causes
  • 3 Ovary insufficiency
    • 3.1 Premature ovarian insufficiency[2]
    • 3.2 Turner syndrome[3]
      • 3.2.1 12-13 years old
        • Preferred regimen (1): Depot 17-β estradiol 0.2–0.4 mg IM every month
        • Alternative regimen (1): 17-β estradiol 6.25 μg transdermal daily
        • Alternative regimen (2): Micronized 17-β estradiol 0.25 mg PO daily
      • 3.2.2 12.5-15 years old
        • Gradually increase 17-β estradiol dose over about 2 years (e.g., 14, 25, 37, 50, 75, 100, 200 μg daily via patch) to adult dose, as following:
          • Preferred regimen (1): 17-β estradiol 100–200 μg transdermal daily
          • Preferred regimen (2): Micronized estradiol 2–4 mg PO daily
          • Preferred regimen (3): Ethinyl estradiol 20 μg PO daily
          • Preferred regimen (4): Conjugated equine estrogen 1.25–2.5 mg PO daily
      • 3.2.3 14-16 years old
        • Preferred regimen (1): Micronized progesterone 200 mg PO daily on the 20th–30th days of monthly cycle
        • Preferred regimen (2): Micronized progesterone 200 mg PO daily on the 100th–120th days of 3-month cycle 
  • 4 Chronic anovulation

Oral contraceptive pills (OCPs)

  • Different studies have shown that OCP therapy can slow down the bone loss process in patients with exercise- and anorexia-associated amenorrhea. The detailed results are as following table:[13]
Type of amenorrhea Medicine Dosage Treatment duration Bone mineral density (BMD) site Outcome
Exercise-associated
functional amenorrhea 		Ethinyl estradiol 0.035 mg 12 months Lumbar spine and femoral neck Increased BMD in all sites[14]
Norethindrone
Medroxyprogesterone 		0.5-1.0 mg
10 mg
Ethinyl estradiol 0.03 or 0.02 mg 12 months Lumbar spine Increased BMD in all sites[15]
Desogestrel 0.15 mg
Ethinyl estradiol 0.030 mg 10 months Lumbar spine and legs Increase BMD in lumbar spine not in legs[16]
Levonorgestrel 0.150 mg
Ethinyl estradiol 0.05 mg 8 months Lumbar spine and radius Increase BMD in lumbar spine not in radius[17]
Cyproterone acetate 2 mg
Conjugated estrogen 0.0625 mg 24 months Lumbar spine and femoral neck Increased BMD in all sites[18]
Transdermal estradiol 0.05 mg
12 days Estriol 1 mg 9.3 months Lumbar spine, femoral neck, and trochanter No change BMD in any sites[19]
Estradiol 2 mg
10 days Estriol 1 mg
Estradiol 2 mg
Norethisterone 1 mg
6 days Estriol 0.5 mg
Estradiol 1 mg
Premarin 0.625 mg 24 months Lumbar spine, wrist, and foot Increase BMD in lumbar spine, neither in wrist nor in foot[20]
Provera 10 mg
Ethinyl estradiol 0.035 mg 10 months Lumbar spine and femoral neck Increase BMD in lumbar spine not in femoral neck[21]
Norgestimate 0.180–0.250 mg
Anorexia-associated
functional amenorrhea 		Ethinyl estradiol 0.020–0.035 mg 12 months Lumbar spine and femoral neck No change BMD in any sites[22]
Norgestimate
Norgestrel
Norethindrone acetate
Levonorgestrel 		0.180–0.250 mg
0.5 mg
0.5-1.0 mg
-
Ethinyl estradiol 0.05 mg 12 months Lumbar spine No change BMD[23]
Norgestrel 0.5 mg
Premarin 0.625 mg 18 months Lumbar spine No change BMD[24]
Provera 5 mg
Ethinyl estradiol 0.035 mg
Premarin 0.3–0.625 mg daily 4.3 years Lumbar spine and femoral neck Increased BMD in all sites[25]
Ethinyl estradiol 0.020 mg 12 months Lumbar spine and femoral neck No change BMD in any sites[26]
Levonorgestrel 0.1 mg
Dihydroepiandrostendion (DHEA) 50 mg daily
Recombinant IGF-1 30 mg/kg twice daily 9 months Lumbar spine, femoral neck, and radius No change BMD in any sites[27]
Ethinyl estradiol 0.035 mg
Norethindrone 0.4 mg
Ethinyl estradiol 0.035 mg 13 cycles Lumbar spine and femoral neck No significant change BMD in any sites[28]
Norgestimate 0.180–0.250 mg

Androgen therapy

  • Recent studies have shown that androgen therapy in the dose of 50, 100, or 200 mg of micronized DHEA daily may increase bone mineral density (BMD), and prevent osteoporotic fracture. However, there is no established long term study to prove this effect.[26]

Recombinant insulin like growth factor 1 (IGF-1)

Recombinant leptin

Bisphosphonates

Medicine Dose Treatment duration Bone mineral density (BMD) site Outcome
Etidronate 200 mg daily 3 months Tibial midshaft Non-significant increase in BMD in all sites[31]
Calcium 600 mg daily
Vitamin D 1 μg daily
Risedronate 5 mg 9 months Lumbar spine and femoral neck Increase BMD in lumbar spine not in femoral neck[32]
Calcium 1500 mg
Vitamin D 400 IU
Alendronate 10 mg 12 months Lumbar spine and femoral neck Non-significant increase in BMD in all sites[30]
Calcium 1200 mg
Vitamin D 400 IU

References

  1. ↑ Ortiz LD, Syro LV, Scheithauer BW, Rotondo F, Uribe H, Fadul CE; et al. (2012). "Temozolomide in aggressive pituitary adenomas and carcinomas". Clinics (Sao Paulo). 67 Suppl 1: 119–23. PMC 3328813. PMID 22584716.
  2. ↑ "Committee Opinion No. 698: Hormone Therapy in Primary Ovarian Insufficiency". Obstet Gynecol. 129 (5): e134–e141. 2017. doi:10.1097/AOG.0000000000002044. PMID 28426619.
  3. ↑ Bondy, Carolyn A. (2007). "Care of Girls and Women with Turner Syndrome: A Guideline of the Turner Syndrome Study Group". The Journal of Clinical Endocrinology & Metabolism. 92 (1): 10–25. doi:10.1210/jc.2006-1374. ISSN 0021-972X.
  4. ↑ Dickey RP, Taylor SN, Curole DN, Rye PH, Pyrzak R (1996). "Incidence of spontaneous abortion in clomiphene pregnancies". Hum. Reprod. 11 (12): 2623–8. PMID 9021363.
  5. ↑ Harborne L, Fleming R, Lyall H, Norman J, Sattar N (2003). "Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome". Lancet. 361 (9372): 1894–901. doi:10.1016/S0140-6736(03)13493-9. PMID 12788588.
  6. ↑ Balasch J, Fábregues F, Creus M, Casamitjana R, Puerto B, Vanrell JA (2000). "Recombinant human follicle-stimulating hormone for ovulation induction in polycystic ovary syndrome: a prospective, randomized trial of two starting doses in a chronic low-dose step-up protocol". J. Assist. Reprod. Genet. 17 (10): 561–5. PMC 3455454. PMID 11209536.
  7. ↑ Steiner AZ, Terplan M, Paulson RJ (2005). "Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis". Hum. Reprod. 20 (6): 1511–5. doi:10.1093/humrep/deh840. PMID 15845599.
  8. ↑ Sabuncu T, Harma M, Harma M, Nazligul Y, Kilic F (2003). "Sibutramine has a positive effect on clinical and metabolic parameters in obese patients with polycystic ovary syndrome". Fertil. Steril. 80 (5): 1199–204. PMID 14607575.
  9. ↑ Jayagopal V, Kilpatrick ES, Holding S, Jennings PE, Atkin SL (2005). "Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome". J. Clin. Endocrinol. Metab. 90 (2): 729–33. doi:10.1210/jc.2004-0176. PMID 15536162.
  10. ↑ Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, O'Keefe M, Ghazzi MN (2001). "Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial". J. Clin. Endocrinol. Metab. 86 (4): 1626–32. doi:10.1210/jcem.86.4.7375. PMID 11297595.
  11. ↑ Wang CF, Gemzell C (1980). "The use of human gonadotropins for the induction of ovulation in women with polycystic ovarian disease". Fertil. Steril. 33 (5): 479–86. PMID 6768596.
  12. ↑ Glueck, C.J; Wang, Ping; Fontaine, Robert; Tracy, Trent; Sieve-Smith, Luann (2001). "Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS)11The full text of this article is available via JAH Online". Journal of Adolescent Health. 29 (3): 160–169. doi:10.1016/S1054-139X(01)00202-6. ISSN 1054-139X.
  13. ↑ Vescovi JD, Jamal SA, De Souza MJ (2008). "Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature". Osteoporos Int. 19 (4): 465–78. doi:10.1007/s00198-007-0518-6. PMID 18180975.
  14. ↑ Hergenroeder AC, Smith EO, Shypailo R, Jones LA, Klish WJ, Ellis K (1997). "Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months". Am. J. Obstet. Gynecol. 176 (5): 1017–25. PMID 9166162.
  15. ↑ Castelo-Branco C, Vicente JJ, Pons F, Martínez de Osaba MJ, Casals E, Vanrell JA (2001). "Bone mineral density in young, hypothalamic oligoamenorrheic women treated with oral contraceptives". J Reprod Med. 46 (10): 875–9. PMID 11725730.
  16. ↑ Rickenlund A, Carlström K, Ekblom B, Brismar TB, Von Schoultz B, Hirschberg AL (2004). "Effects of oral contraceptives on body composition and physical performance in female athletes". J. Clin. Endocrinol. Metab. 89 (9): 4364–70. doi:10.1210/jc.2003-031334. PMID 15328063.
  17. ↑ De Crée C, Lewin R, Ostyn M (1988). "Suitability of cyproterone acetate in the treatment of osteoporosis associated with athletic amenorrhea". Int J Sports Med. 9 (3): 187–92. PMID 2970444.
  18. ↑ Cumming DC (1996). "Exercise-associated amenorrhea, low bone density, and estrogen replacement therapy". Arch. Intern. Med. 156 (19): 2193–5. PMID 8885817.
  19. ↑ Gibson JH, Mitchell A, Reeve J, Harries MG (1999). "Treatment of reduced bone mineral density in athletic amenorrhea: a pilot study". Osteoporos Int. 10 (4): 284–9. doi:10.1007/s001980050228. PMID 10692976.
  20. ↑ Warren MP, Brooks-Gunn J, Fox RP, Holderness CC, Hyle EP, Hamilton WG, Hamilton L (2003). "Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: a longitudinal study". Fertil. Steril. 80 (2): 398–404. PMID 12909505.
  21. ↑ Warren MP, Miller KK, Olson WH, Grinspoon SK, Friedman AJ (2005). "Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study". Contraception. 72 (3): 206–11. doi:10.1016/j.contraception.2005.03.007. PMID 16102557.
  22. ↑ Golden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, Shenker IR (2002). "The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa". J Pediatr Adolesc Gynecol. 15 (3): 135–43. PMID 12106749.
  23. ↑ Muñoz MT, Morandé G, García-Centenera JA, Hervás F, Pozo J, Argente J (2002). "The effects of estrogen administration on bone mineral density in adolescents with anorexia nervosa". Eur. J. Endocrinol. 146 (1): 45–50. PMID 11751066.
  24. ↑ Klibanski A, Biller BM, Schoenfeld DA, Herzog DB, Saxe VC (1995). "The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa". J. Clin. Endocrinol. Metab. 80 (3): 898–904. doi:10.1210/jcem.80.3.7883849. PMID 7883849.
  25. ↑ Karlsson MK, Weigall SJ, Duan Y, Seeman E (2000). "Bone size and volumetric density in women with anorexia nervosa receiving estrogen replacement therapy and in women recovered from anorexia nervosa". J. Clin. Endocrinol. Metab. 85 (9): 3177–82. doi:10.1210/jcem.85.9.6796. PMID 10999805.
  26. ↑ 26.0 26.1 Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS (2002). "Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial". J. Clin. Endocrinol. Metab. 87 (11): 4935–41. doi:10.1210/jc.2002-020545. PMID 12414853.
  27. ↑ 27.0 27.1 Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A (2002). "Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa". J. Clin. Endocrinol. Metab. 87 (6): 2883–91. doi:10.1210/jcem.87.6.8574. PMID 12050268.
  28. ↑ Strokosch GR, Friedman AJ, Wu SC, Kamin M (2006). "Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study". J Adolesc Health. 39 (6): 819–27. doi:10.1016/j.jadohealth.2006.09.010. PMID 17116511.
  29. ↑ Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS (2004). "Recombinant human leptin in women with hypothalamic amenorrhea". N. Engl. J. Med. 351 (10): 987–97. doi:10.1056/NEJMoa040388. PMID 15342807.
  30. ↑ 30.0 30.1 Golden NH, Iglesias EA, Jacobson MS, Carey D, Meyer W, Schebendach J, Hertz S, Shenker IR (2005). "Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial". J. Clin. Endocrinol. Metab. 90 (6): 3179–85. doi:10.1210/jc.2004-1659. PMID 15784715.
  31. ↑ Nakahara T, Nagai N, Tanaka M, Muranaga T, Kojima S, Nozoe S, Naruo T (2006). "The effects of bone therapy on tibial bone loss in young women with anorexia nervosa". Int J Eat Disord. 39 (1): 20–6. doi:10.1002/eat.20197. PMID 16231362.
  32. ↑ Miller KK, Grieco KA, Mulder J, Grinspoon S, Mickley D, Yehezkel R, Herzog DB, Klibanski A (2004). "Effects of risedronate on bone density in anorexia nervosa". J. Clin. Endocrinol. Metab. 89 (8): 3903–6. doi:10.1210/jc.2003-031885. PMID 15292325.

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