pathophysiology of ovarian failure

2. By
Prof .Refaat Alshimy
AlAzhar University
20092009

4. Premature ovarian failure (POF(
Premature ovarian failure (POF) , sometimes called
premature ovarian insufficiency, occurs when the ovaries
(the twin female organs that produce and release an egg
each monthly cycle ) stop working before a women turns
40 years
When they stop working , women do not ovulate or
produce normal amounts of the hormone estrogen,
Puts them at risk for serious conditions such as
osteoporosis and heart disease , as well as infertility
Gonway ,2000
Definition

5. Pathophysiology
Most women experience the natural loss of
ovarian function, the event we call
menopause, between the age of 45 and 55
years ,with little variation in this figure
between different countries and different
ethnic groups .This age range reflects the
individual variation in biological ageing of
the ovaries between different women.

6. A constant number of resting
primordial follicles enter the
growth phase at any given time,
independent of pituitary
gonadotropins
Later stages of maturation require
FSH and LH
Follicles either mature to ovulation
or become atresic
Ovarian Structure

7. Ovaries have about 2 million primordial follicles at birth
(Ovarian reserve!):
each containing a primary oocyte
By puberty:
number drops to about 250,000 - 400,000
400 oocytes ovulated during
the reproductive years
In the absence of LH/FSH, follicles
undergo atresia
Once follicles are depleted,
ovarian hormone production
declines

8.  Johnson et al. (2004) have challenged the concept
that each woman is endowed with an
irreplenishable number of gametes in the ovary.
 They came to a conclusion that ovarian germ cells
are a dynamic population and undergo constant
renewal.
 Such a novel concept that challenges the central
dogma in reproductive sciences is likely to stir a
flurry of debate and to be followed by further
studies exploring the issue.

9. Age-related rise and fluctuation in FSH

10. Normal menopause vs. POF
Normal menopause is an irreversible condition
,whereas approximately 50% of women with POF
experience intermittent ovarian function after
their periods initially stop
Some women will produce estrogen intermittently
and may ovulate (fluctuating ovarian function )
Pregnancies have occurred after the diagnosis of
POF (5-10%)

11. Primary ovarian failure:
A women never ovulates and never experiences
natural menstruation
Secondary ovarian failure:
Menstruation occurs for months to years , but
then stops prematurely as ovaries have failed
Types

12. Prevalence
* 1% of women under the age of 40
* 0.1% of women under 30
* 0.01% of women under 20
 10- 28 % of women with 1ary amenorrhea
 4 – 18 % of women with 2Ry amenorrhea
 4 – 31 % of all cases with POF are familial
Taylor, 2001

13. Causes of POF
* Etiology unknown, extremely
heterogeneous
in more than 90% of cases,
apart from
● Surgery
● Chemotherapy
● Radiotherapy
● Turner syndrome

14. Causes
Causes of POF in 352 women attending the
Middlesex Hospital , London ,UK
n %
Idiopathic ( including autoimmune) 204 58
Turner's Syndrome 82 23
Chemotherapy 24 7
Familial POF 15 4
Pelvic surgery 8 2
46xy gonadal dysgenesis 7 2
Galactosaemia 6 2
Pelvic irradiation 6 2
Goswami et al 2007
Horm Res 2007; 68 : 196-202

15. Spontaneous POF
No identifiable cause of POF
Unexplained early degeneration of the cells of the
ovary
Common for woman with spontaneous POF to have a
family history of POF in either her mother or sister
The American Collage of obstetrics and gynecology
now recommends that women with POF without
known cause be screened for FMR1 premutations
obstet Gynecol 2006

16. Genes and POF
Various genetic mechanisms implicated in
pathogenesis of POF include
Reduced gene dosage
Non-specific chromosome effects that impair meiosis
These can lead to ovarian failure by causing
Decrease in the pool of primordial follicles
Increased atresia of the ovarian follicles due to apoptosis
or failure of follicle maturation

17. Genes and POF
Identify women / families with POF and risk
of transmission of a genetic disorder
Familial cases in 15- 20 % of cases
Chromosomal abnormalities are detected in
40- 50 % of women who do not experience
spontaneous puberty
Most common genetic abnormality causing
POF is Turner's Syndrome

18. Early follicular loss :Turner's Syndrome

19. X chromosome deletion
Rossetti et al 2004
Inherited deletion of X chromosome in mother
and two daughters
Mother menopause at 43 years
Daughters menopause at 17 and 22 years
Role of environment

20. Genes Implicated in POF
Gene Gene locus
X chromosome BMP15 Xp11.2
Genes FMR1 Xq27.3
FMR2 Xq28
POF1b Xq21.1 – q23.3
Autosomal FSH receptor 2p21 – p16
Genes LH receptor 2p21
Inhibin A 2q33 – q36
FOX1.2 3q22 – q23
GALT 9p13
FSH beta variant 11p13
EIF2b2,4 and 5 14q24.3, 2p23.3,3q27
POLG 15q25
NOGGIN 17q22
LH-B 19q13.32
AIRE 21q22.3
_______________________________________________________________________

21. Autoimmunity and POF
POF may be due to an abnormal self-recognition by
the immune system
autoimmune mechanisms are involved in pathogenesis
of up to 30% of cases of POF
Clinically, autoimmune ovarian failure is broadly
discussed in two scenarios:
In association with autoimmune Addison's disease
Isolated or associated with other autoimmune diseases
Betterle et al ., 2002

22. POF and Addison's disease
2–10% of POF cases are known to be
associated with adrenal autoimmunity.
POF precede Addison's disease by 8–14 years.
Sharing of auto antigens between ovary and
adrenal glands, particularly the side-chain
cleavage enzyme may explain the association
of ovarian failure and Addison's disease.

23. POF in absence of Addison's disease
Thyroid autoimmunity is the most common association
Thyroid autoimmunity 20 - 40 % ( Belvisi et al. 2006 )
Insulin-dependent diabetes mellitus (IDDM)
Myasthenia gravis has also been reported
(Ryan and Jones, 2004)
Women with SLE, anti-ovarian antibodies were detected
in 84% (Moncayo-Naveda et al., 1989)

24. Autoimmunity and POF
POF is reported to be associated with endocrine and non-
endocrine autoimmune disorders
Endocrine
thyroid, adrenal, hypoparathyroid , diabetes mellitus, and hypophysitis
Non-endocrine
chronic candidiasis, idiopathic thrombocytopenic purpura, vitiligo,
alopecia, autoimmune haemolytic anaemia, pernicious anaemia,
systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease,
Sjögren's syndrome, myasthenia gravis, primary biliary cirrhosis and
chronic active hepatitis
POF may be part of the autoimmune polyglandular
syndromes (APS)

25. Autoimmunity and POF
Possible antigenic targets for antibody mediated
autoimmune damage in POF
Steroid producing cells (SCA)
3ß-hydroxysteroid dehydrogenase (3ß-HSD)
autoantibodies
Gonadotrophin receptors blocking antibodies
Other ovarian antigens
 Corpus luteum
 Zona pellucida and oocyte

26. Autoimmunity and POF
None of these antibody assays has been validated to
confirm a clinical diagnosis of autoimmune POF ???
1- Serological marker of autoimmunity may not be present
despite the disease being autoimmune in nature due to
decline in the quantity of auto antigen
2- Many auto antigens of organ-specific autoimmune diseases
like POF may be still unidentified
Therefore in the clinical work up of POF, screening for
an autoimmune etiology is only possible in practice by
looking for coexisting autoimmune diseases

27. Miscellaneous Causes of POF
Viral oophoritis
Mumps oophoritis
Cigarette smoking and epilepsy
Endocrine disruptors, heavy metals,
solvents, pesticides, plastics, industrial
chemicals

28. Miscellaneous Causes of POF
Radiotherapy
Effect of radiotherapy is dependent on dose ,age and on
the radiation therapy field
Complete ovarian failure occurs with a dose of 20 Gy in
women under 40 years of age and with only 6 Gy in older
women
Prepubertal ovary is relatively resistant to gonad toxicity
due to radiotherapy and chemotherapy
Ovariopexy preserves ovarian function in 60-100% of
patients
Beerendonk and Breat , 2005

29. Miscellaneous Causes of POF
Chemotherapy
Gonadotoxic effect of chemotherapy is largely
drug and dose-dependent and is related to age
Alkylating agents increase the risk of POF by a
factor of 9
Teenagers receiving chemotherapy have a 4 times
increased risk of POF
This risk is increased by a factor of 27 among
women aged 21-25 years
Hascalik et al., 2004

30. Sonmezer, M. et al. Oncologist 2006;11:422-434
Alkylating agents are
extremely gonadotoxic
because they are not
cell cycle-specific and
can damage resting
primordial follicles,
whereas cycle-specific
agents such as MTX
and 5-FU do not have
any effect on ovarian
reserve
Degree of gonadal failure associated
with chemotherapeutic agents

31. Miscellaneous Causes of POF
Pelvic surgery has the potential to damage
the ovary by affecting its blood supply or
causing inflammation in the area
Uterine artery embolization may also lead to
POF by compromising the vascular supply to
the ovary
Razayi et al 2004

32. Presentation
Amenorrhea
Oligomenorrhoea / menstrual dysfunction
Infertility
Estrogen – deficiency symptoms
Pubertal delay / primary amenorrhea

33. POF-Symptoms
Baber ,Abdalla and Studd (1991)
Vasomotor 76%
Loss of libido 31%
sexual enjoyment reduced 37%
Most Distressing symptom
Loss of fertility 54%
Feeling Older 27%

34. POF Symptoms
Girls who have POF before puberty do not
experience the classic symptoms of estrogen
deficiency as exposure of the body to adult
levels of estrogen and subsequent estrogen
loss appear to be necessary for the
development of symptoms
Young women who develop POF after puberty
frequently experience symptoms of estrogen
deficiency

35. Consequences of POF
Estrogen – deficiency
- Symptoms
- Long – term effects
Bone Loss
Heart Disease
Infertility
Psychological needs

36. What are the Impacts of Estrogen Decline?

37. Management
Make and explain the diagnosis
Treat symptoms
Prevent long – consequences
Address psychological needs
Genetic counseling if appropriate
Treat infertility
Offer long – term follow – up and support

38. Make the diagnosis
Diagnosis of POF is often delayed ,
even with classic symptoms of
menopause
Alzubaidi 2002
POF is often a fluctuating condition
Ovarian dysfunction precedes POF

39. Make the diagnosis
Early diagnosis of familial POF will provide
the opportunity to predict the likelihood of
early menopause, and allow other reproductive
choices to be made, such as freezing embryos
or having children earlier.
Because POF has cumulative effects over
time, it is important for clinicians to make a
timely diagnosis and begin appropriate
strategies for management

40. Diagnostic tests
Elevated FSH levels in menopausal rang (usually
above 40 IU/I), PLUS a low estrogen level ( usually
below 20 picogram /ml ) must be detected on at
least two separate occasions each at least one
month apart for a firm diagnosis to be made
Ultrasound
Ovarian biopsy
Both do not alter the management
Khastair 1994 , WHP Monash Uneversity 2007

41. Investigations
Prolactin, androgens
Thyroid function
Screen for thyroid and adrenal auto antibodies
Karyotype (early onset POF before age of 30)
Genetic screen for FRAXA
Cell surface markers on peripheral blood lymphocytes
could result in diagnosis of autoimmune POF before the
development of complete ovarian failure

42. HRT
Which type?
What dose?
What duration?

43. HRT
Long-term HRT is needed for relief of
menopausal symptoms.
Prevent long-term health sequel of estrogen
deficiency, such as osteoporosis and possibly
coronary heart disease.
WOMEN with premature ovarian failure should
be informed that standard hormone therapy does
not provide effective contraception.

44. Choice of HRT for women with POFUK Soc Paediatric Endocrinology 42 questionnaires (28 responses)
COCP 18 (64%)
Oral HRT (sequential) 5 (18%)
Transdermal HRT (sequential) 3 (11%)
Ethinyloestradiol (sequential) 2 (7%)

45. HRT type
With the oral and transdermal routes there is a
choice between continuous or sequential
delivery
Continuous regimen avoids menstrual flow but
break through bleeding may be more common
Sequential regimen ensures monthly menstrual
bleed, which may be a psychological benefit to
some young women (and absurd to others!).

46. HRT type
Oral estrogen
 Conjugated equine estrogen
 17ß –oestradiol
Have consistent and comparable effects on hot flashe
Have similar short-term adverse effects
Nelson, 2004.

47. HRT type
Transdermal estrogen
 Avoids first-pass liver metabolism
 Has rapid onset and termination of action
 Attainment of therapeutic hormone levels with
low daily doses
 Appears to be free of an excess risk of thrombosis

48. HRT type
Hormone Implants
 Higher Circulating oestradiol
 More effective Symptom control
 Better skeletal effects
 Better effects on uterus?
 Placement of 25-50mg oestradiol pellets usually in
the lower abdomen or buttocks in a minor office
procedure

49. HRT type
Some young women with POF find the combined
oral contraceptive pills a more acceptable option
Provides a fixed combination of estrogen and
progesterone with a ‘pill free week’ which contrasts
from the greater flexibility with the HRT alternatives
The pill-free week amounts to 3 months of
estrogen deficiency each year
Nelson , 2004

50. OCP vs. HRT
Synthetic • Physiological
More potent • May be safer for long time
Pill – free week • Continuous estrogen
Like peer-group • Stigma of HRT
Reminder of infertility • Not
contraceptive

51. HRT dosage
An HRT regimen should be based on
the individual preferences of each
patient who should be encouraged to
undertake a trial and error approach
through the wide variety of products
available

52. HRT dosage
Standard HRT doses may be suboptimal
In young women HRT may not be enough
Expectation for sexual function can be higher
 Vaginal moisturisers
 Topical estrogen
Monitor by symptoms and BMD
- Oestradial levels useful only for implants to determine the time
of re-dosing, which is about every 6 months for most women

53. Choice of progesterone
Progestins vary from the more potent such as
norethisterone to the weaker such as
dydrogesterone
 The route may be oral, transdermal or uterine
With the oral and transdermal routes there is a
choice between continuous or sequential (for
10-14 days each month)

54. Choice of progesterone
Uterine delivery with the levonorgestrel
intrauterine device (Mirena) has the
advantage of avoiding the adverse effects
of oral progestins highlighted in the
studies of older women
Chlebowski et al. 2003

55. Testosterone
Androgen level decrease in POF
(half of testosterone supply from ovaries )
Hartman 1997
Reduced libido, sexual function , ? Energy ? BMD
Worse in oophorectomised women
Transdermal testosterone administration and
dehydroepiandrosterone treatment are two of the
options for androgen replacement in these women
s/e excess hair growth and acne
Braunstein 2005, shifren 2007

56. Alternative to HRT
Efficacy lower than HRT:
 Serotonin and noradrenalin re- uptake inhibitors
 Clonidine
 Gabapentin
• Efficacy unproven:
 Progesterone transdermal cream
 Phyto-oestrogens ( soy, red clover)
• Safety unproven:
 Herbal preparation
e.g. black cohosh , dong qui
Panay and rees RCOG 2006

57. lifestyle
 Smoking increase risk of POF
Chang 2007
Exercise , especially weight bearing ,
Improves bone mass
Wallace 2000
Diet , calcium and vitamin D
Jackson 2006
Alcohol and caffeine

58. Long- term risks of POF
Life expectancy reduced
Rocca et al lancet oncol 2006
Cohort of > 12, 000 women
 2 years less life expectancy if menopause < 40
 Increase mortality ischemic heart disease
 Reduced uterine and ovarian cancer
Osseward et al Epidemiology 2005 .16 : 556

59. Long- term risks of POF (2)
May clinic cohort study – bilateral
oophorectomy
1950 -1987 followed to 2006
Premature death
Cardiovascular disease
Cognitive impairment , dementia , parkinsonism
Osteoporosis and fracture
Decrease psychological wellbeing
Decrease sexual function
Shuster et al Menopause int
2008

60. Osteoporosis prevention
HRT prevents bone loss
HRT improves BMD in POF
Little evidence on alternative in POF
 Bisphosphonates used in breast cancer
 Calcium and vitamin D
Davis 1990, Van der Voort 2003

61. Cardiac disease
 Vascular endothelial dysfunction
associated with oestrogen – deficiency
 Improved by HRT Kalantaridou 2004 , Osberg 2007
 Increased risk of ischemic heart disease
following BSO Atsma 2006, Allison 2008
 Lack of long – term data on HRT for POF

62. Women’s Health Initiative (WHI)
JAMA 2002;288:321-333
Two parallel RCT
Study 1
8506 women received HRT
(0.625mg CEE+2.5mg MPA)
8102 received placebo
Study 2
Oestrogen alone Vs placebo
Women with menopausal symptoms or osteoporosis
needing HRT not recruited into study.

63. Benefits and risks
 WHI Women studies are
not applicable to young women
 No data are available to evaluate the impact of
treatment on risk factors, such as the development
of breast cancer or of cardiovascular events in
young women with POF and extrapolation from
studies in older women may not always be
appropriate.

64. HRT duration
Until expected age of
menopause
“In women who have experienced a premature menopause
(due to ovarian failure , surgery , or other causes ) HRT
may be used for treatment of menopausal symptoms and
for prevention of osteoporosis until the age of 50 years.
After this age , therapy for prevention of osteoporosis
should be reviewed and HRT considered a second choice”

65. Fertility
“ The sudden switch from
fertile women to irrevocably
infertile women was the
biggest blow of all”

66. Spontaneous pregnancy
Pregnancy rate 5 – 10 %
Can occur on HRT
Miscarriage rate ? 20 %
Van Kasteren 1999
Prognostic factors :
 Recent diagnosis – short period of amenorrhea
 Fluctuating FSH
 Ovarian activity on ultrasound
 POF due to autoimmunity or chemotherapy

67. Fertility treatment
Treatment strategies unproven:
 Stimulation after FSH suppression
 Corticosteroids
 All were reported to be equally ineffective
Review in 194 patients, 3 pregnancies
Recovery of ovarian function may occur after
regression of the autoimmune status
Van Kasteren 1999

68. Fertility horizons
 Germ cells in BM – unproven
 “Bone marrow transplantation generates immature
oocytes and rescues long – term fertility in a
preclinical mouse model of chemotherapy- induced
POF”
Johnson& Tilly 2005 , Lee 2007
 Cloning ?
 Artificial gametes ?

69. Egg donation
Good success rates ( up to 50 %)
Donated oocytes has been used to achieve
pregnancy in women with POF since 1987
Wide variation in availability
Recipient needs HRT to prepare uterus
Donor undergoes IVF stimulation cycle

70. Risks to egg donor
Risks of stimulation
 OHSS
 (hormone – dependant conditions )
Pregnancy
Risks of egg collection
 Bleeding
 Infection

71. Pregnancy risks
Multiple birth
Pre- eclampsia
Turner syndrome
Cancer survivors :
 Cardiac / renal toxicity of chemotherapy
 Uterine irradiation : misc. , IUGR, pre- term

72. Surrogacy
May be required after gynecological
cancer or uterine irradiation
 IVF with “full “ surrogacy (donated eggs)
 Insemination (surrogate is egg donor)

73. Prevention of POF
 Lower hysterectomy rate
 Fertility- preserving surgery for cancer
 Less gonad toxic chemotherapy regimens
 ? Hormonal protection ( GnRH-a )
 Embryo , egg and tissue freezing

74. 18 women, 15-40 yrs, Hodgkin’s or non-Hodgkin’s lymphomas
Chemotherapy + LHRH-a
historical matched control group of 18 women (17-40 yrs)
treated with chemotherapy alone
COMPARED TO:

75. ASCO Recommendations on Fertility
Preservation in Cancer Patients
(Expert Panel, J Clin Oncol 2006)
 At this time, since there is insufficient
evidence regarding the safety and effectiveness of
GnRH analogs and other means of ovarian
suppression on female fertility preservation, women
interested in ovarian suppression for this purpose
are encouraged to partecipate in clinical trials

76. Embryo Cryopreservation
It is the only established
method for fertility preservation
Survival rates per thawed embryos are in
the range of 35%–90%, implantation rates are in
the range of 8%–30%, and cumulative pregnancy
rates exceed 60%
(Sonmezer et al, 2004).

77. Egg freezing
Pregnancy rate 10 – 20 % per transfer with
conventional freezing
Higher with vitrification
no long – term safety data
? 500 births in total
Tur- Kaspa ASRM 2007

78. Ovarian tissue freezing
Still experimental
Cycle – independent
Possible in pre-pubertal patient
4 live births reported
Donnez et al,2004
Future ? IVM ? Whole ovary graft

79. Psychology
POF is an extremely devastating life experience
 Women with POF report
 High levels of depression
 Low levels of self-esteem with negative effects on sexuality
 Moderate to severe stress at the time of diagnosis
Crises arise some years after the original
diagnosis, for instance when a near relative
achieves a pregnancy

80. Perspective
Genome scanning for familial cases
Genome scanning for sporadic cases
Candidate genes from animal models ?

81. Genes
of menopause
New contraceptive targets
New infertility treatment

82. Conclusions
 POF is a complex condition that requires specialist
services.
 The diagnostic workup is aimed at determining the
etiology where possible and is followed by a screen
for syndromic conditions.
 Estrogen replacement and fertility options need to
be reassessed at intervals and clinicians have to be
vigilant for psychological sequelae.
 Encourage HRT at least until 51 yrs.
 No increased risk of breast cancer.

83. POF Recommendations
 Improve awareness.
 Multi- disciplinary clinical services.
 Incorporate psychology & associate with
“late effects “ service in cancer centers.
 Multicentre research collaboration.
 ? Guidelines.