ANOVULATORY BLEEDING

An ovu lat ory bleedin g i s t h e st an dard t erm in olog y u sed t o describe bleedin g f rom t h e
u t erin e

en dom et riu m as a resu l t of a dy sf u n ct ion in g m en st ru al sy st em , speci f ical ly ex clu

din g an an at om ic

lesion of t h e u t eru s.

1, 29

An ovu lat ory bleedin g i s al so ref erred t o as dy sf u n ct ion al or i rreg u lar u t erin e

bleedin g .

Epidemiology

An ovu lat ory bleedin g i s t h e m ost com m on f orm of n on cy cl ic u t erin e bleedin g .

Th e m ost com m on

cau se i s PCOS, f or wh ich t h e prevalen ce rat es ran g e f rom 6% t o 8%.

43–45

I n f act , PCOS i s t h e m ost

com m on en docrin e abn orm al i t y am on g U .S. wom en of reprodu ct ive ag e.

45

PCOS can presen t as a

variet y of m en st ru at ion di sorders, in clu din g am en orrh ea, m en orrh ag ia, an d/or an ovu
lat ory bleedin g .

Al t h ou g h i t s ex act def in i t ion con t in u es t o evolve, i t i s a di sorder of an drog en ex

cess t h at of t en

in clu des poly cy st ic ovarian m orph olog y an d ovu lat ory dy sf u n ct ion . I t i s a sig n i f ican t
ri sk f act or f or

t h e m et abol ic sy n drom e, t y pe 2 diabet es, dy sl ipidem ia, h y pert en sion , an d possibly

cardiovascu lar

di sease.

21, 46, 47

PCOS i s a com m on cau se of ovu lat ion dy sf u n ct ion in adu l t wom en .

21
Ot h er com m on

cau ses in adu l t wom en in clu de h y perprolact in em ia, h y pot h alam ic am en orrh ea, al so k
n own as

h y pog on adot ropich y pog on adi sm , prem at u re ovarian f ai lu re, an d t h y roid dy sf u n ct ion .

1, 29

Etiology

Wh en con siderin g t h e et iolog y of an ovu lat ory bleedin g , t h e pat ien t ’ s ag e m u st be

con sidered. Al l

pat ien t s presen t in g wi t h abn orm al bleedin g sh ou ld be evalu at ed f or preg n an cy . Most

adolescen t s wi l l

ex perien ce ph y siolog ic an ovu lat ory cy cles in t h e f i rst f ew y ears f ol lowin g m en arch e
becau se t h ei r

h y pot h alam ic–pi t u i t ary –g on adal ax i s i s st i l l m at u rin g . However , i f an adolescen t h

as n ot developed

reg u lar m en st ru al cy cles wi t h in 5 y ears of m en arch e, f u rt h er evalu at ion f or t h e cau

se, su ch as PCOS,

sh ou ld be con sidered.

48

An ovu lat ory cy cles m ay “u n m ask ” an u n derly in g bleedin g di sorder . Wh en

i rreg u lar m en ses i s associat ed wi t h sig n i f ican t bleedin g , an in h eri t ed bleedin g di

sorder sh ou ld be a

con sidered cau se, especial ly in adolescen ce.

6, 29

W om en ex perien cin g an ovu lat ion in t h ei r

reprodu ct ive y ears sh ou ld be evalu at ed f or pat h olog ic cau ses, in clu din g PCOS, t h y roid
dy sf u n ct ion ,

h y perprolact in em ia, prim ary pi t u i t ary di sease, prem at u re ovarian f ai lu re, h y pot h alam
ic dy sf u n ct ion ,

di sordered eat in g , adren al di sease, an d an drog en -produ cin g t u m ors. W om en in t h ei r

perim en opau sal

y ears m ay ex perien ce “ph y siolog ic” an ovu lat ory cy cles becau se of in t erm i t t en t ly decl
in in g est rog en
level s. Reg ardless of ag e, evalu at ion f or en dom et rial h y perplasia an d/or en dom et rial
can cer sh ou ld

be con sidered wh en a wom an ex perien ces ex cessive bleedin g wi t h an ovu lat ory cy cles.
Wh en

con siderin g t h e et iolog y of an ovu lat ion , i t i s com m on f or several con di t ion s t o coex
i st (e.g ., PCOS

an d h y pot h y roidi sm ), each con t ribu t in g t o t h e wom an ’ s con st el lat ion of sy m pt om

s. Al l com m on

et iolog ies sh ou ld be con sidered wh en beg in n in g t o evalu at e an ovu lat ion .

Pathophysiology

Norm al m en st ru al cy cles occu r t h rou g h a com plex in t eract ion of t h e h y pot h alam u
s, pi t u i t ary g lan d,

ovaries, an d en dom et riu m (Fig . 63-1). I n an ovu lat ory cy cle, t h e ovary produ ces a m at
u re, est rog en -secret in g f ol l icle in respon se t o FSH release f rom t h e pi t u i t ary . Th e en
dom et riu m prol i f erat es u n der

t h e in f lu en ce of t h i s est rog en produ ct ion . At a cri t ical level of est rog en con cen t rat
ion , t h e pi t u i t ary

respon ds by produ cin g an “L H su rg e,” wh ich creat es a cascade of ovarian even t s, cu lm

in at in g in

ovu lat ion . U pon oocy t e release, t h e f ol l icle becom es a prog est eron e-produ cin g corpu s
lu t eu m . Th e

en dom et riu m “org an iz es” in t o secret ory en dom et riu m in t h e presen ce of adequ at e
prog est eron e. I f

con cept ion an d im plan t at ion do n ot occu r , corpu s lu t eu m in volu t ion cau ses a decl in
e in est rog en an d

prog est eron e leadin g t o predict able, org an iz ed m en st ru al f low as t h e en dom et riu m slou g h
s.

I f ovu lat ion does n ot occu r, prog est eron e i s n ot produ ced, an d t h e en dom et riu m wi l l con
t in u e t o

prol i f erat e in an “u n org an iz ed” f ash ion u n der t h e in f lu en ce of con t in u ed est rog en
produ ct ion .

Even t u al ly t h e en dom et riu m wi l l becom e so t h ick t h at i t can n o lon g er be su pport ed by

con t in u ed
est rog en produ ct ion . Th i s resu l t s in u n org an iz ed, sporadic slou g h in g of t h e en dom et riu
m,

ch aract eri st ic of t h e u n predict able an d h eavy bleedin g of an ovu lat ion . An ovu lat ion h as
several

et iolog ies. I n adolescen ce, h y pot h alam ic–pi t u i t ary ax i s im m at u ri t y con t ribu t es t o t h e
absen ce of t h e

L H su rg e requ i red f or ovu lat ion . I n t h e an orex ic pat ien t , t h e h y pot h alam u s loses m u ch
of i t s pu l sat i le

Gn RH release, leadin g t o low level s of FSH an d L H, en ou g h f or est rog en produ ct ion bu t n ot

en ou g h

t o in du ce ovu lat ion .

TREATMENT

Opt im iz in g an ovu lat ory bleedin g t h erapy depen ds on accu rat e iden t i f icat ion of t h e
di sorder ’ s

cau se(s). Th e t reatm en t opt ion s f or an ovu lat ory bleedin g are wide an d varied.

Desired Outcome

Con t rol of ex cessive bleedin g in t h e sh ort -t erm i s param ou n t . L on g er-t erm g oal s of
t h erapy in clu de

rest orin g t h e n at u ral cy cle of orderly en dom et rial g rowt h an d sh eddin g ,

29, 49

decreasin g an ovu lat ion

com pl icat ion s (e.g ., ost eopen ia, in f ert i l i t y ), an d im provin g overal l qu al i t y of l i f e. T
able 63-2

iden t i f ies t h e ag en t s u sed t o m an ag e an ovu lat ory bleedin g an d t h ei r recom m en ded

doses.

General Approach to Treatment

Al t h ou g h t h e appropriat e prim ary t reatm en t ch oice f or an ovu lat ory bleedin g depen ds
on t h e accu rat e

diag n osi s of i t s cau se an d iden t i f icat ion of desi red ou t com es, addi t ion al t reatm en t
m ay be n ecessary

t o m an ag e ot h er sig n s an d sy m pt om s. T reatm en t t o resolve an ovu lat ory bleedin g sh

ou ld be in i t iat ed

an d an y u n derly in g m en orrh ag ia sh ou ld be m an ag ed.

Nonpharmacologic Therapy

Non ph arm acolog ic t reatm en t opt ion s f or an ovu lat ory bleedin g depen d on t h e u n derly
in g cau se. I n a

wom an of reprodu ct ive ag e wi t h PCOS, m oderat e weig h t loss of 2% t o 5% m ay resu l t

in im proved

m en st ru al reg u lari t y an d ovu lat ory f u n ct ion , redu ced h i rsu t i sm , in creased in su l in
sen si t ivi t y , an d

im proved respon se t o f ert i l i t y t reatm en t s.

21

I n wom en wh o h ave com plet ed ch i ldbearin g or wh o h ave

n ot respon ded t o m edical m an ag em en t , en dom et rial ablat ion or resect ion an d h y st

erect om y are

su rg ical opt ion s. Procedu re ch oice in volves sh ared deci sion m ak in g wi t h t h e pat ien t . I
n t h e sh ort

t erm , ablat ion resu l t s in less m orbidi t y an d sh ort er recovery periods. However , a sig n i f
ican t n u m ber

of wom en even t u al ly u n derg o h y st erect om y in t h e su bsequ en t 5 y ears.

29

Pharmacologic Therapy

Est rog en i s t h e recom m en ded t reatm en t f or m an ag in g acu t e severe bleedin g epi

sodes becau se i t

prom ot es en dom et rial st abi l iz at ion .

49

Fol lowin g i t s in i t ial u se t o con t rol acu t e bleedin g epi sodes,

t h erapy con t in u at ion m ay be n ecessary t o preven t f u t u re occu rren ces. OC u se f u l f i

l l s t h i s role an d

con t ribu t es t o predict able m en st ru al cy cles.

OCs preven t recu rren t an ovu lat ory bleedin g by providin g a prog est in an d su ppressin g
ovarian

h orm on es an d adren al an drog en produ ct ion . Th ey al so, in di rect ly , in crease sex h orm on e-
bin din g

g lobu l in (SHBG). SHBG bin ds an drog en s an d redu ces t h ei r ci rcu lat in g f ree con cen t rat ion s.
For
wom en wi t h h ig h an drog en level s an d i t s relat ed sig n s su ch as h i rsu t i sm (e.g ., t h ose wi t
h PCOS) OCs

con t ain in g less t h an or equ al t o 35 m cg of et h in y l est radiol an d a prog est eron e t h at ex h

ibi t s m in im al

an drog en ic side ef f ect s (e.g ., n org est im at e an d desog est rel ) or wi t h an t ian drog en ic ef f ect
s (e.g .,

drospi ren on e) m ay be desi rable.

20

CLINICAL PRESENTATION Anovulatory B leeding

Ge ne ral

• Pat ien t s m ay or m ay n ot be in acu t e di st ress

Symptoms

• I rreg u lar, h eavy , or prolon g ed vag in al bleedin g , perim en opau sal sy m pt om s (h ot f lash es,
n ig h t s

sweat s, vag in al dry n ess)

Si gns

• Acn e, h i rsu t i sm , obesi t y

Laboratory Te sts

• I f PCOS i s su spect ed, con sider f ree or t ot al t est ost eron e, f ast in g g lu cose, f ast in g l ipid pan
el

• I f perim en opau se i s su spect ed, m easu re FSH

• Th y roid-st im u lat in g h orm on e

Othe r Di agnosti c Te sts

• I f t h e pat ien t i s older t h an 35 y ears, en dom et rial biopsy

• Pelvic u l t rasou n d t o evalu at e f or poly cy st ic ovaries

• I f perim en opau se i s su spect ed, m easu re FSH

Clinical Controversy…

OCs con t ain in g an t ian drog en ic prog est eron es are very ef f ect ive f or m an ag in g t h e
acn e an d

h i rsu t i sm t h at accom pan y PCOS; t h ey al so su ppress ovarian an drog en produ ct ion an

d in crease
sex h orm on e-bin din g g lobu l in , t h u s redu cin g f ree t est ost eron e con cen t rat ion s. Con t
roversy

reg ardin g t h ei r u se in PCOS ex i st s secon dary t o t h ei r pot en t ial adverse ef f ect s on in

su l in

resi st an ce, g lu cose t oleran ce, vascu lar react ivi t y , an d coag u labi l i t y .

20

An in crease in h ig h -sen si t ivi t y C-react ive prot ein (a predict or of cardiovascu lar di sease)
an d an in crease in

h om ocy st ein e level s (in dicat in g an in creased ri sk of cardiovascu lar di sease) h ave been

observed wi t h t h e u se of su ch OCs.

50

An ot h er t rial f ou n d a redu ct ion in brach ial art ery f low-m ediat ed di lat at ion an d an in
crease in carot id in t im a-m edia t h ick n ess, bot h in dicat ors of

en dot h el ial dy sf u n ct ion , f ol lowin g t h erapy wi t h OCs con t ain in g et h in y l est radiol
an d

cy prot eron e acet at e.

51

Addi t ion al , lon g er-t erm cl in ical t rial s wi l l clari f y wh et h er t h e ben ef i t s of

t h ese ag en t s ou tweig h t h e ri sk s. I t h as been su g g est ed t h at cardiovascu lar ri sk

calcu lat ors be

em ploy ed as an adju n ct t o g u idel in es su g g est in g t h e u se of OCs in t h i s pat ien t popu lat

ion .

52

I n wom en wi t h con t rain dicat ion (s) t o est rog en or in wh om t h e side ef f ect s are u n accept
able,

prog est eron e-on ly produ ct s are an opt ion . Th ey sh ou ld be st ron g ly con sidered f or wom en

ex perien cin g m en orrh ag ia associat ed wi t h an ovu lat ory bleedin g .

53

I n wom en wi t h PCOS, depot an d

in t erm i t t en t oral MPA provide en dom et rial prot ect ion t h rou g h en dom et rial sh eddin g .

I f preg n an cy i s
n ot a desi red ou t com e of t reatm en t , an ot h er prog est eron e opt ion i s placem en t of a levon
org est rel -con t ain in g I U D.

29, 53

Met f orm in an d t h e t h iaz ol idin edion es, in clu din g piog l i t az on e an d rosig l i t az on e, im
prove in su l in

sen si t ivi t y . I n pat ien t s wi t h PCOS, t h i s con t ribu t es t o redu ced ci rcu lat in g an drog en con
cen t rat ion s,

in creased ovu lat ion rat es,

5, 54, 55

an d im proved g lu cose t oleran ce.

5, 21

Th ese im provem en t s occu r du e t o

t h e SHBG in crease t h at occu rs via in creased in su l in sen si t ivi t y . Met f orm in an d t h iaz ol
idin edion e

u se f or an ovu lat ory bleedin g associat ed wi t h PCOS i s ben ef icial n ot on ly f or an ovu lat ory
bleedin g

an d f ert i l i t y bu t al so f or im provin g g lu cose t oleran ce an d ot h er m et abol ic param et ers t h

at con t ribu t e

t o cardiovascu lar ri sk .

5, 21, 56

For wom en desi rin g preg n an cy , m et f orm in i s preg n an cy cat eg ory B, an d

piog l i t az on e an d rosig l i t az on e are cat eg ory C.

Clinical Controversy…

Th e overal l role of m et f orm in in t reat in g PCOS an d i t s du rat ion of t h erapy rem ain con t
roversial .

For ovu lat ion in du ct ion , dat a sh ow t h at m et f orm in i s h ig h ly ef f ect ive in bot h clom
iph en e ci t rat e-resi st an t pat ien t s an d pat ien t s u sin g i t as in i t ial t h erapy .

54, 55

I t s u se t h rou g h ou t preg n an cy h as

been associat ed wi t h a redu ct ion in early preg n an cy loss rat es.

57

Th e presen ce of dy sl ipidem ia
an d h y perin su l in em ia in creases t h e lon g -t erm ri sk f or developin g cardiovascu lar di
sease in

PCOS pat ien t s. Cu rren t research in dicat es t h at m et f orm in sh ou ld be con sidered t o

redu ce

cardiovascu lar ri sk in t h ese wom en .

56

More research i s n eeded t o def in i t ively iden t i f y t h e

role(s) of m et f orm in in PCOS, part icu larly as i t relat es t o ovu lat ion in du ct ion .

I f t h e t reatm en t g oal i s im proved f ert i l i t y via ovu lat ion in du ct ion , clom iph en e ci t rat e i
s an opt ion .

Treatm en t wi t h 50 m g /day f or 5 day s can be in i t iat ed between m en st ru al cy cle day s 3 an d

5. Th i s

of t en occu rs af t er in du cin g wi t h drawal bleedin g wi t h a prog est eron e su ch as MPA 10 m g

dai ly oral ly

f or 10 day s. I f ovu lat ion does n ot occu r wi t h t h i s dose of clom iph en e, a dose of 100 m g /day
is

warran t ed. I n rare in st an ces, i t m ay be in creased by 50 m g in crem en t s u p t o 250 m g /day .

Drug Tre atme nts of F i rst Choi c e

As wi t h m an y m en st ru at ion -relat ed di sorders, t h ere i s n ot on e u n iversal t reatm en t

opt ion of f i rst

ch oice f or an ovu lat ory bleedin g . Rat h er , t h e t reatm en t (s) ch osen depen ds on accu rat
e et iolog ic

diag n osi s as wel l as iden t i f icat ion of t h e desi red t reatm en t ou t com e(s).

OCs are t h e f i rst -ch oice t reatm en t in wom en wi t h an ovu lat ory bleedin g wh o do n ot desi re

preg n an cy .

22

Th e u se of OCs con t ain in g et h in y l est radiol an d a prog est eron e wi t h m in im al an drog en ic

or an t ian drog en ic ef f ect s i s ef f ect ive f or cy cle con t rol an d m in im iz in g t h e an drog en ic sig
n s an d

sy m pt om s of PCOS.

20, 47, 49
Relat ive t o an ovu lat ion in wom en wi t h PCOS, in su l in -sen si t iz in g ag en t s in clu din g m et f
orm in an d

t h e t h iaz ol idin edion es im prove ovu lat ory f requ en cy an d m et abol ic param et ers. Clom iph en
e u se m ay

f u rt h er assi st in ach ievin g ovu lat ion in du ct ion .

More recen t dat a su pport even f u rt h er m et f orm in ’s u se com pared t o clom iph en e f or ovu lat
ion

in du ct ion .

54, 55

Met f orm in f or ovu lat ion in du ct ion

54

as wel l as i t s u se t h rou g h ou t preg n an cy

57

in

wom en wi t h PCOS h as been associat ed wi t h redu ced m i scarriag e rat es in t h i s pat ien t popu
lat ion .

Spe c i al P opul ati ons

An ovu lat ory cy cles are f ai rly com m on in t h e perim en arch al reprodu ct ive y ears. Ovu lat ion t
y pical ly i s

est abl i sh ed 1 y ear or m ore f ol lowin g m en arch e. An ovu lat ory bleedin g occu rrin g in t h
i s popu lat ion

m ay be ex cessive. I f ex cessive bleedin g occu rs, t h e pat ien t sh ou ld be evalu at ed f or

bleedin g

di sorders. Th e prevalen ce of bleedin g di sorders, in clu din g von W i l lebran d’ s di sease, prot
h rom bin

def icien cy , an d idiopat h ic t h rom bocy t open ia pu rpu ra, in t h i s popu lat ion ran g es f rom 5% t
o 24%.

I f iden t i f ied, t h e speci f ic bleedin g di sorders sh ou ld be t reat ed. Acu t e severe bleedin g can be

m an ag ed wi t h h ig h -dose est rog en . OCs con t ain in g less t h an or equ al t o 35 m cg of et h in y

l est radiol i s

a f i rst -l in e t reatm en t in adolescen t s wi t h ch ron ic an ovu lat ion .

49

Drug Cl ass Informati on

T able 63-3 iden t i f ies t h e sig n i f ican t ph arm acolog ic propert ies t h at requ i re m on i t orin
g f or t h e ag en t s

u sed t o t reat an ovu lat ory bleedin g .

P e rsonal i z e d P harmac othe rapy

Wh i le n ot t y pical ly an i ssu e am on g t h e relat ively y ou n g popu lat ion of pat ien t s t

reat ed wi t h m et f orm in

f or PCOS, on e m u st be cog n iz an t of t h e ri sk of lact ic acidosi s in m et f orm in u sers

wi t h ren al

im pai rm en t . As su ch , t h i s dru g sh ou ld be avoided in wom en wi t h seru m creat in in e

>1.4 m g /dL (124

μm ol /L ).

Evaluation of Therapeutic Outcomes

T able 63-3 l i st s t h e ex pect ed ou t com es an d speci f ic m on i t orin g param et ers f or t h e

t reatm en t

m odal i t ies u sed t o m an ag e an ovu lat ory bleedin g .