1. The Climacteric Woman
treatment options in 2006 :
what has experience taught me
Manuel Neves-e-Castro, MD
Lisbon, Portugal, 2006

2. I am
- a normal human being
- a medical doctor
- a feminologist (gender medicine)
- a gynecologist
- an endocrinologist

4. But... certainly I am not
a menopausologist ...

5. Is there a Menopausal
Medicine?
There is only ONE Medicine (L.Speroff)
There are only TWO Medicines (MNC):
a BAD Medicine and
a GOOD Medicine

6. Therefore,
what we must learn,is…
how to practice a
GOOD
MEDICINE!
mnc/05

7. Looking after a menopausal woman is a
most
fascinating,
gratifying and
complex
vivid experience in the life of a physician.
MNC/05

8. • It is fascinating – because one is dealing
with the holistic dimension of a woman’s
life where there is the interplay of her
macro and micro social environments, of
her self and her id , and of all her body
functions.
MNC/05

9. • It is gratifying – because the help of a
physician who is well aware of that holistic
dimension may lead to very positive
results in terms of the quality of her life,
that are the best reward for a health care
giver.
MNC/05

10. • It is complex – because the abundance of
specific medical literature, and its often
misinterpreted results, leads to a climate of
scare of potential risks that overcomes the
known benefits of treatments.
MNC/05

11. Definition
A Climacteric woman
is a woman (gender based medicine)
is an aging person (geriartrics)
is perimenopausal (hormone deficient)

12. Managing by
Objectives:

13. Critical Objectives
a) The diagnosis of health
b) The identification of risk factors
c) The presence of symptoms
• gender related
• age related
• hormone related

14. Critical Objectives
d) The treatment of symptoms
e) The elimination of risk factors
f) The diagnosis of diseases
g) The treatment of diseases

15. Specific Objectives
(S.O.)
1. CV and metabolic
a) obesity
b) dislipidemias
c) hypertension
d) insulin resistance

16. S.O.
2. CNS
a) vasomotor symptoms
b) mood, sleep
c) sexual disfunctions, libido

17. S.O.
3. Bone
a) osteoarticular

18. S.O.
4. Reproductive organs
- vaginal discharges
- atrophic vaginitis
- fibroids
- meno and metrorrhagia

19. S.O.
5. Breast
lumps and tenderness

20. S.O.
6. Bladder
incontinence
chronic cystitis

21. S.O.
7.Contraception

22. S.O. Targets
1. exercise
2. nutrition
3. mental health
4. sexual conseling
5. pharmacotherapy
a) hormonal
b) non-hormonal

23. S.O. Treatments
P, E+P, E
Androgens
Ca + vit D
bisfosfonates, strontium
Statins, IACE, diuretics, α and β blockers
aspirin
psychotherapy
Serm’s
tibolone
gabapantin
routes, schemes

24. Causes of Death Among Women*
Other Cancers
Heart Disease
15%
Breast Cancer 34%
4%
Diabetes 3%
Chronic Lower 6%
Respiratory
Disease
28% 10%
Other Cerebrovascular
Disease
*Percentage of total deaths in 1999 among women aged 65 years and older.
Anderson RN. Natl Vital Stat Rep. 2001;49:1-13.

25. In the light of present evidence,
doctors and women should be
reassured that the suggested HT’s for
the relief of symptoms in the
menopause
are safe and very effective

26. There are controversies about the
present management of the
climacterium which are due to:
• a lack of culture that prevents a correct
criticism of the published results
• a bad practice of medicine that ignores the
woman in her totality
• political lobbies from the NIH
• a lack of scientific honesty manifested by
many of the WHI writers
• lobbies from several pharmaceutical
industries through the activities of many well
known doctors that “offer” themselves to transmit
their “messages”

28. Many women taking hormones were
urged by their physicians to stop taking
these medications immediately or
decided to stop taking them on their own.
Petitti DB. JAMA. 2005;294:245-246.

29. Based on the WHI study group,
implementation of the results
into clinical practice has little, if
any, scientific basis.
Adam Ostrzenski and Katarzyna M Ostrzenska. Am J Obst Gynecol
2005;193:1599-604

30. The applicability of the WHI
findings to women between age of
51.1 and 56.1 years and younger is
unknown.
Ostrzenski A and Ostrzenska KM.
Am J Obst Gynecol 2005;193:1599-604

31. “W I: Now that the dust has settled…”
H
• To publish data that may or may not
be entirely true or certainly
premature is a disservice to the
medical profession and, most
important, to our patients.
• The majority of the data that were
published is not statistically
significant even at the nominal level.
Creasm W et al. Am JObst Gynecol 2003;189:621-626
an T.

32. “Lessons from the WHI”
“…most articles and broadcast segments
tended to focus exclusively on either the sm all
absolute risks or the larger relative risks,
neglecting the more even-handed picture that
presented both.
Since the sharply increased relative risks got
the most play, news coverage about the trial’s
findings had an alarming cast.”
De nz e r S. Editorial. A I rn M d . 2 0 0 3 ; 1 3 8 : 3 5 2 -3 5 3
nn nte e

33. Biased opinions
be they pro or con,
dishonor the profession
and
harm our patients.
Sacket DL. The arrogance of preventive medicine. Can Med Assoc J
2002;167:363-364

34. NNH / Year
(Number Needed to Harm)
Coronary Heart Disease
W (RR 1.29)
HI 1428
HERS (RR 0.99) 5000
Breast Cancer
W (RR 1.26)
HI 1250
HERS (RR 1.27) 833
MNC

35. Effects of conjugated Equine Estrogen in Postmenopausal Women
with Hysterectomy.JAMA, 2004;291:1701-1712

38. Stroke
“In women 50-59 years not taking HT,
ischemic stroke is expected to occur in
3 out of 1000 women during 5 years.
Five years use of HT would yield 1
additional case of stroke/ 1000 women”
EMAS Statement; 2004.

41. Then, why all this noise?...
Mainly because the conclusions of
recent trials were severely misinterpreted
by the medical professionals, the media
and by the women, themselves
MNC/05

42. “We are drowing in information,
but starved for knowledge”
John Naisbilt

43. Practioners are guided:
• by the best available information that
can be extrapolated with validity to
their patients,and
• by their acumulated experience
MNC/05

44. Public Health doctors are guided by
what epidemiologists suggest ...
but ...
Most epidemiologists only establish
associations of events and seldom
determine cause/effect relationships
MNC/05

45. thus ...
both,the practitioners who act as if they
were public health doctors,
and the public health doctors who act
as if they were clinicians,
should not overemphasize the
epidemiological associations of events
that are not necessarily cause/effect
findings

46. But ... today ...
many • Act in their offices as if they
were public health doctors...
practitioners
many
public health doctors • Act in their departments as if
they were clinicians ...
This is wrong!

47. Effect on the risk of CHD
WHI Significant increased risk
RR 1.29 (CI 1.02-1.63); 29 % increased risk
AR 0.37% vs 0.30% (ie, 37 vs 30 events
annually per 10.000 women)
HERS Nonsignificant decreased risk
RR 0,99 (CI 0.84-1.17); 1% decreased risk
AR 3.66% vs 3.68% (ie, 366 vs 368 events
annually per 10.000 women)

48. Hormones and the Heart
1 in 3 women will die from coronary heart
disease (CHD) in the USA.
1 in 25 women will die from breast cancer
Fitzpatrick LA. JCEM 2003;88(12):5609-10

49. “HRT is associated with a
35% reduction in mortality
for women who suffered
myocardial infarction”.
Shlipack MG, Angeja B, Go AS, et al Circulation 2001;104:2300-2304

50. Hormone replacement therapy:
where to now?
Recent studies suggest HRT may inhibit
the process of atherosclerosis in
healthy arteries soon after menopause,
and observational studies in younger
women starting HRT suggest a potential
cardiovascular benefit
Mikkola TS, Clarkson TB. Cardiovasc Res 2002;53:605-19.

51. Recent reports did not find, for
continuous combined treatments, any
increased risk of either CHD or breast
cancer.
The difference from WHI being that
women were younger, symptomatic
and with lower body weights
Heikkinen J. NAMS 2004, Abstract LB38
Lobo R. Arch Int Med 2004;164:482-484

52. • Manson et al reported a nonstatiscally
significant decreased relative risk of
cardiovascular events in hormone
therapy users who were <10 years from
the onset of menopause.
Manson JE et al. JAMA 2002;288:321-33

53. Hormone therapy for younger
postmenopausal women: how can we
make sense out of the evidence?
At the moment, I believe we can say with
relative certainty that hormone therapy in
younger postmenopausal women
results
in lower coronary heart disease events
and total mortality.
Salpeter S. Climacteric 2005;8:307-310

54. Younger Women May Receive Heart Protection From
Estrogen Therapy
In women ages 50-59 who had undergone a
hysterectomy, a significant protective effect of
estrogen treatment, when both primary (heart
attacks and heart attack death) and secondary
(coronary artery bypass surgery, angioplasty,
confirmed angina pectoris) cardiac endpoints
were considered.
Dr. S. Mitchell Harman, director and president of Phoenix-based
Kronos Longevity Research Institute (KLRI) in Archives of Internal
Medicine 2006;106:357-363

55. WHI Study
WHI investigators reported a statistically
significant (34%) lower risk for the combined
endpoint of myocardial infarction (heart attack),
coronary death, coronary revascularization and
confirmed angina among women who were
between the ages of 50 and 59 at the start of
the study (RR 0.66; 95% CI 0.45-0.96).
Hsia J et al.Arch Intern Med 2006;166:357-363

56. Press Statement IMS
The estrogen plus progestogen arm of the WHI
and the estrogen-alone arm actually showed that
HT does not
increase the risk of coronary heart disease in
the peri- and early menopause,
and may even carry beneficial effects.
Feb 2006

57. Press Statement IMS
Also, in a subgroup of women demographically
similar to those in the WHI, there was no
significant relation between HT and CHD among
women who initiated therapy at least 10 years
after the menopause
(RR = 0.87, 95% CI 0.69–1.10 for estrogen alone;
RR = 0.90, 95% CI 0.62–1.29 for estrogen with progestogen).
Feb 2006

58. Press Statement IMS
The WHI study was not designed, and
therefore was not powered, to investigate the
consequences of hormone therapy (HT) in
women below 60 years of age. Therefore,
any attempt to present the results of the study
as indicating that HT may inflict damage to the
heart in general – a message that was accepted
by many medicalsocieties and regulatory Authorities
is simply wrong and must be amended.

59. Hsia J, Langer RD, Manson J et al. Conjugated equine estrogens and coronary heart
disease. Arch Int Med 2006;166:357-65

60. Hsia J, Langer RD, Manson J et al. Conjugated equine estrogens and coronary heart
disease. Arch Int Med 2006;166:357-65

61. Hsia J, Langer RD, Manson J et al. Conjugated equine estrogens and coronary heart
disease. Arch Int Med 2006;166:357-65

62. Breast Cancer

63. Menopausal women and their
doctors are scared about the side
effects of HRT
mainly about breast cancer
MNC/05

64. Hormone replacement therapy and
breast cancer: estimate of risk
Extended use of estrogen for
10 years increases risks by 0,5% ,and by
15 years increases risks by 0,9%
upon cessation of HRT, the relative risk
quickly returns to 1.0 !
Coombs N J, Taylor R, Wilcken N. Boyages J. BMJ 2005;331:347-349

65. Breast cancer and the use of HRT
Considering 10.000 women on the
combination HRT then for each year
there would be:
Seven additional cases of heart attacks
Eight cases of stroke,
Eight cases of pulmonary embolus,
Eight cases of invasive breast cancer,
Six fewer cases of hip fractures
Baum M. The Breast 2005;14-178-80

66. Breast cancer survival and the use
of HRT
It must be emphasized that we are
talking about an increased incidence of
the disease, which does not
automatically translate into an increase
in deaths from the disease.
Baum M. The Breast 2005;14:178-80

67. Many Doctors fail to persuade
them to go on with HRT, in
despite of telling that the
benefits are far greater than
any potential risk
MNC/05

68. Breast Cancer
• The doubling time of an initial cancer
cell ,up to the diagnosis of a resultant
1cm tumor ,is most likely greater than
10 years.
• This is why many dormant cancer cells
may exist in a“normal” breast !
MNC/05

69. Breast Cancer
• The diagnosis of a breast cancer after the
initiation of a HRT (with a duration of less than 5
years) is only a proof of its growth stimulatory
effect (not of its carcinogenic effect)
• Therefore, the reversal of the risk to 1 after the
cessation of HRT confirms again only its growth
promoting effect and denies a carcinogenic
effect.
Dietel M., Lewis MA. and Shapiro S. Human Reproduction 2005;20:2052-60

70. Occult Breast Cancer
Clinically occult in situ
BC’s are frequent in
young and middle-aged
women.
Nielsen M et al-Br J Cancer 1987;56:814-9

71. Occult Breast Cancer
Breast malignancy was
found in 22 women
(20%)
Nielsen M et al-Br J Cancer 1987;56:814-9

72. Thus…
• Mammographies give more false
negative than false positive results !
• A “normal” mammography does not
exclude the presence of cancer cells
that may “explode” a few months later…
MNC/05

73. Estrogen replacement therapy in
patients with early breast cancer
The mortality rates from breast cancer for
the ERT users was 4.28% compared with
22.3% in the nonusers.
Natrajan PK and Gambrell RD. Am J Obstet Gynecol 2002;187:289-95

74. “Recurrent breast cancer was
found in 9% of HRT users
and 15% of nonuser”.
O’Meara ES et al

75. Mortality following development of
breast cancer while using
oestrogen or oestrogen plus progestin:
a computer record-linkage
study
W Chen, DB Petitti and AM Geiger.
British Journal of Cancer (2005) 93, 392 – 398

76. This study explored survival after
exposure to oestrogen or oestrogen
plus progestin at or in the year prior to
breast cancer diagnosis
oestrogen plus progestin users had lower
all-cause mortality and breast cancer
mortality
Chen W, Petitti DB and Geiger AM. British Journal of Cancer 2005
93, 392-398

77. Breast cancer survival after hormone
exposure

78. Overall survival after hormone
exposure

79. Breast cancer survival after hormone
exposure

80. Overall survival after hormone
exposure

81. A menopausal woman expects
from her attending physician
to be receptive to all of her complains,
to understand her psychic and physical
concerns,
to support her insecurity and
to help overcome her crisis.
MNC/05

82. One may easily conclude that
without an adequate technique of
communication, using the proper
language,
there is no possible help
Thus,
physicians must acquire expertise in
the technique of communication
MNC/05

83. Talking about
Risks...

84. Are there risks?
It is crucial that information be given
about the difference between relative
risks and absolute risks, since the latter
are the major cause of misinformation and
alarmism, being the favorites of the
media…
MNC/05

88. Nurses’s Health Study
from 1980 to 1994 CHD ↓ 31%
↓ Smoking ↓ 13%
↑ Obesity ↑ 8%
↑ THS ↓ 9%
↑ Better nutrition ↓ 16%
Hu FB, Grodstein F et al. Trends in the Incidence of Coronary Heart
Disease and Changes in Diet and Lifestyle in Women. NEJM
2000;343:530-537.

89. “It appears that half of the
benefits in the prevention of
cardiovascular diseases are
not hormone related”!
Mosca L, Grundy SM, Judelson D, et al. Circulation 99;99:2480-4

90. Can side effects be minimized ?

91. First of all, there are many different
post-menopausal hormone
therapies: different estrogens,
different progestins, different
routes of administration, different
regimens, which have different
profiles.
Neves-e-Castro M. Maturitas 2001;38(3):235-237

92. Second, there are those who know
and those who do not know to
tailor-make it to a particular woman
and to monitor its efficacy in the
targets that have justified its
selection.
Neves-e-Castro M. Maturitas 2001;38(3):235-237

93. Third, there are those who think
that the menopause is a disease to
be treated solely with sex
hormones, and there are those
who believe that the menopause is
an event in a mid-aged woman’s
life.
Neves-e-Castro M. Maturitas 2001;38(3):235-237

94. Hippocrates promoted specific
diets to prevent and cure
diseases such as illnesses of
the heart.
Lyons AS et al. In Medicine: an illustrated History. New York:Abradale
Press,1990:20719

95. The Polymeal
Franco O et al. BMJ 2004;329:1447-50

96. Doctors could retrain as
Polymeal chefs or wine advisers
The Polymeal—an evidence based menu that
includes wine, fish, dark chocolate, fruits,
vegetables, garlic, and almonds—promises to be an
effective, safe, cheap, and tasty solution to reducing
cardiovascular morbidity and increasing life
expectancy.
Polymeal could reduce cardiovascular disease by
more than 75%.
Franco O et al. BMJ 2004;329:1447-50

97. The Polypill
Wald N and Law M. BMJ 2003;326:1419-25

98. Wald N and Law M. BMJ 2003;326:1419-25

99. A strategy to reduce
cardiovascular disease by more
than 80%
One third of people taking this pill from age 55
would benefit, gaining on average about 11
years of life free from an IHD event or
stroke.
Wald N and Law M. BMJ 2003;326:1419-25

100. Moderate exercise cuts breast
cancer biomarkers in
postmenopausal women
Increased physical activity significantly
reduces serum estrogens in
postmenopausal women and thus may
reduce the risk of breast cancer.
McTiernan A. Cancer Res 2004;364:2923-8

101. Aspirin could be used to prevent
cancer
Three recently published studies indicate
that aspirin, already enjoying a second
lease of life in the prevention of heart
disease, may soon become a first line of
defense against cancer.
London O. BMJ 2003;326:565

102. “Not everything that can be
counted counts;
and not everything that
counts can be counted”
Albert Einstein

103. “There are no really “safe”
biological active drugs.
There are only “safe”
physicians”
K inetzy H 1 9 9 3
am A

104. ?

105. In conclusion …
and to make a long story
short…

106. What are the best recommendations of
the climacteric woman’s doctor?
1. Understand what is happening to the body during
the climacteric and the postmenopause
2. Mental occupation
3. Physical exercise
4. Proper nutrition (moderate consumption of red
wine, and abundant fish, vegetables, fruits, soy,
milk, garlic, chocolate, etc)
5. Keep the body mass index (BMI) within normal
limits
6. Keep a normal girdle/hip ratio, waist circumference
7. Refrain from smoking
8. Keep a normal blood pressure
9. Keep the blood lipids within normal values
(statins?)
10. Examine the breasts (palpation, inspection,
mammography)

107. My Message is:
.To prescribe postmenopausal hormonal
treatments when clinically indicated, if
not contraindicated
. No answers from ongoing clinical
trials are indispensable to practice
today a good Medicine
MNC/05

108. Let us not medicalize the
Menopause..
instead…
Let us holistically
approach the Climacteric
and Aging Women.
MNC /05

109. To know the disease a woman has
is as important as
to know the woman who has the
disease
William Osler

110. “Each time we learn something new,
the astonishment comes from the
recognition that we were wrong
before.
In truth, whenever we discover a new fact, it
involves the elimination of old ones.
WE ARE ALWAYS, as it turns out,
fundamentally IN ERROR.”
Lewis Thomas English Biologist (1913-1993)

111. What about the best treatments
during the climacterium and
beyond?
There is a general tendency to consider
that sex steroid hormones are the only
instruments with which to treat women
when they enter in the climacteric phase
of their lives…
MNC/05

112. What about the best treatments
during the climacterium and
beyond?
However, little attention is paid to other
pharmacological interventions (non
hormonal) and strategies that have been
shown to be important for the
prevention of such diseases and to
maintain or improve health.
MNC/05

113. Which is the best treatment?
In general terms, is the one that is wisely
indicated, if not contraindicated, after
balancing benefits and risks, of all strategies
and interventions, hormonal or not.
It must be aimed at specific objectives and
targets that will be monitored at regular intervals
in order to determine its efficacy and to estimate
the occurrence of any side effects, a condition
that will determine its duration.
MNC/05

114. Which is the best treatment?
Patient needs and preferences are decisive, based on
the doctors’ advice. Let it not be forgotten that although
many treatments are available, they are nevertheless
not indispensable. Doctors have the duty to give their
best unbiased information to their patients so that they
may make the right choices and then be compliant.
The woman is the decision maker, if the doctor sees
no contraindication.
Thus,
the best treatment is what she has
chosen.
MNC/05

115. The conclusions of these studies suggest that
the “safe “ woman (NNH between 600-1000
women) to initiate HT is
- between 50-59 years of age
- with vasomotor symptoms
- less than 10 years after the menopause
- being treated with statins
- with a good lipid profile and
- with a Body Mass Index >25
Neves-e-Castro M. Human Reproduction 2003;18:2512-2518

116. This is precisely the profile of the
great majority of women who come
for consultation after their
menopause.
Therefore it seems that what most
gynecologists are doing to their
predominant population of patients is
not unsafe and contributes not only
to a good quality of life but to
prevention, as well.
Neves-e-Castro M. Human Reproduction 2003;18:2512-2518

117. I personally believe that in the healthy early
post menopausal woman the long term HT’s,
other than relieving vasomotor symptoms,
may play an important role in improving QoL
and in the prevention of CVD, osteoporosis
and Alzheimer, under surveillance.
Systemic estrogens, added when needed to
vaginal progesterone or progestagen loaded
IUD’s, may be very beneficial, largely
overpassing minimal risks.
The well-informed woman will be the only
decision- maker.
MNC/05

118. Continuous combined parenteral
estrogen substitution and
intrauterine progestogen
delivery:the ideal HST
combination?
Wildemeersch D, Janssens D and Weyers S.
Maturitas 2005;51:207-214

119. Continuous intrauterine compared
with cyclic oral progestin
administration in perimenopausal
HRT
This method of HRT with the Lng-IUD’s
as progestin delivery system is
efficient in protecting the endometrium
against hyperplasia, and will make
withdrawal bleedings unnecessary.
Boon J et al. Maturitas 2003;46:69-77

120. Relationship between breast cancer and
use of the levonorgestrel-IUD
These results suggest that the use of the
levonorgestrel-releaing intrauterine system
is not associated with an increased risk of
breast cancer
Backman T et al. Obstet & Gynecol 2005;106:813-7

121. Tibolone improves myocardial
perfusion in postmenopausal
women with ischemic heart
disease: an open-label
exploratory pilot study.
In postmenopausal women with ischemic heart
disease, six months of therapy with tibolone
significantly improved stress myocardial
perfusion and the "amount of ischemia."
Campisi R et al. J Am College Cardiol 2006;47:559-564

122. Postmenopausal hormone therapy: critical
reappraisal and unified hypothesis
83:558-66

123. NAMS position statement on
estrogen and progestagen use in
peri-and postmenopausal women
Revised breast cancer statements indicate
that the risk of breast cancer probably
increases with EPT use but not with ET
use.

124. NAMS position statement on
estrogen and progestagen use in
peri-and postmenopausal women
Place no limit on ET/EPT treatment
duration, provided it is consistent with
treatment goals; if monitored regularly, no
stipulation is made regarding when to
reduce or stop therapy

125. If there are no incoming contraindications
we see no reason to establish a time limit
to the duration of therapy, mainly if there is
a recovery of symptoms after its
discontinuation
Cochrane B, NAMS 2004, P53
IMS www.imsociety.org
NAMS www.menopause.org

126. What has been learned from the
major observational studies and
clinical trials?
the first lesson
systematically administered
progestagens may in part suppress
some of the beneficial effects of
estrogens and may also slightly increase
the risk of breast cancer after treatments
with duration greater than five years.
MNC/05

127. What has been learned from the
major observational studies and
clinical trials?
the second lesson
estrogens, when given alone to
histerectomized women, did not appear to
minimally affect the risk for breast cancer
when compared with controls
MNC/05

128. What has been learned from the
major observational studies and
clinical trials?
the third lesson
Metabolic effects of estrogens and
progestagens, as a whole, can differ
depending on the route of administration, i.e.
oral vs. parentheral, and on the combination of
both, in a sequential regimen or in continuous
combined administration.
MNC/05

129. What has been learned from the
major observational studies and
clinical trials?
the fourth lesson
Hormonal treatments are the first
choice for vasomotor symptom relief
as long as they are needed (on and off
assessment). They should not be used for
the secondary prevention of CVD, when
atheroma plaques are already present.
MNC/05

130. What has been learned from the
major observational studies and
clinical trials?
the fourth lesson (cont.)
Conversely ,they may protect from CVD
if started early during the transition
into the post menopause.
Hormonal treatments are preventive of
osteopenia and osteoporosis at any
stage in life
MNC/05

131. What has been learned from the
major observational studies and
clinical trials?
the fifth lesson
Estrogens may prevent degenerative
lesions of the CNS since, so far, they
seem to be the only available drugs with
nerve growth effects
MNC/05

133. Convictions are more
dangerous enemies of thruth
than lies
Friedrich Wilhelm Nietzsche

134. A WOMAN
in the autumn of her life
deserves an indian summer
rather than a winter of discontent ...
Robert B Greenblatt

135. This is what I have learned