“Carol Davila” University of Medicine & Pharmacy

Bucharest

Puberty.
Menopause. Women’s Ageing
Manuela Russu
Habilitated Professor
Head of “Dr. I. Cantacuzino”
Discipline of Obstetrics & Gynecology

MCR, 2018
 Normal Menstrual Cycle :
a result of coordination of cyclic hormone
production in the
hypothalamo-pituitary-ovarian –uterine axis

when the ischemic

endometrial
lining becomes
necrotic
and sloughs
 Adolescence (A). Puberty (P)
A. period of psychological & social transition
from childhood to adulthood.
A. largely overlaps the period of puberty, but its
boundaries are less precisely defined, & it refers as
much to the psychosocial & cultural characteristics of
development during the teen years as to the physical
changes of puberty
 Puberty (P)
P. refers to the process of physical changes by which a child’s body
becomes an adult body capable of reproduction, initiated by hormone
signals from the brain to the ovaries/testes. In response, the gonads
produce many hormones that stimulate growth, function, or
transformation of brain, bones, muscle, skin, breasts, & reproductive
organs.
→ Growth accelerates in the first half of puberty, & stops at the
completion of puberty.
→ Before puberty, body differences between boys and girls are almost
entirely restricted to the genitalia.
→ During puberty, major differences of size, shape, composition, and
function develop in many body structures & systems.
The most obvious of these are referred to as secondary characteristics
 Puberty onset (1)
Onset is associated with high GnRH pulsing,
with de-inhibition of the pulse generator in the arcuate nucleus of
hypothalamus, which precedes the rise in sex hormones, LH and FSH
Exogenous GnRH pulses cause the onset of puberty.
Brain tumors which increase GnRH output may also lead to premature
puberty.
The inhibition of the arcuate nucleus is an ongoing active
suppression by other areas of the brain.
The signal & mechanism releasing the arcuate nucleus from inhibition
have been the subject of investigation for decades and remain
incompletely understood.
Leptin levels rise throughout childhood & play a part in allowing
the arcuate nucleus to resume operation. If the childhood inhibition of
the arcuate nucleus is interrupted prematurely by injury to the brain, it
may resume pulsatile gonadotropin release and puberty will begin at an
early age.
 Puberty onset (2)

Neurons of the arcuate nucleus secrete GnRH into the blood of the
pituitary portal system. The American physiologist, Ernst Knobil, found
that the GnRH signals from the hypothalamus induce pulsed secretion of
LH (and to a lesser degree, FSH) at roughly 1-2 h intervals. The LH
pulses are the consequence of pulsatile GnRH secretion by the arcuate
nucleus that, in turn, is the result of an oscillator or signal generator in
the central nervous system (" GnRH pulse generator")
In the years preceding physical P, Robert Boyar discovered that the
gonadotropin pulses occur only during sleep, but as P progresses they
can be detected during the day. By the end of P, there is little day-night
difference in the amplitude & frequency of gonadotropin pulses.
Some investigators have attributed the onset of puberty to
a resonance of oscillators in the brain.
By this mechanism, the gonadotropin pulses that occur
primarily at night just before puberty represent beats.
 Puberty onset (3)
An array of "autoamplification processes" increases the
production of all of the pubertal hormones of the hypothalamus,
pituitary, & gonads.
 Regulation of adrenarche and its relationship to maturation of
the hypothalamic-gonadal axis is not fully understood, and
 Some evidence suggests it is a parallel but largely independent
process coincident with or even preceding central puberty.
 Rising levels of adrenal androgens (termed adrenarche) can
usually be detected between 6 and 11 years of age, even before the
increasing gonadotropin pulses of hypothalamic puberty. Adrenal
androgens contribute to the development of pubic hair (pubarche), adult
body odor, and other androgenic changes in both sexes.
 The primary clinical significance of the distinction between
adrenarche and gonadarche is that pubic hair and body odor changes by
themselves do not prove that central puberty is underway for an
individual child.
 Puberty onset (4)
 Menarche (from Greek μήν moon + αρχή beginning) (M)
is the first menstrual period, or first menstrual bleeding in
the females of human beings. From both social and medical
perspectives it is often considered the central event of
female P, as it signals the possibility of fertility.
 Timing of M is influenced by both genetic and
environmental factors, especially nutritional status.
 The average age of menarche has declined over the last
century but the magnitude of the decline and the factors
responsible remain subjects of contention.
 M is the culmination of a series of physiological and anatomic
processes of puberty
 Puberty (P)
Menarche & fertility
 In most girls, menarche does not signal that ovulation
has occurred. In postmenarchal girls, about 80% of
the cycles were anovulatory in the first year after
menarche, 50% in the third and 10% in the sixth year
 Regular ovulation is usually indicated by predictable
and consistent intervals between menses, predictable
and consistent durations of menses, and predictable
and consistent patterns of flow (e.g., heaviness or
cramping).
 Continuing ovulation typically requires a body fat
content of at least 22%. An anthropological term for
this state of potential fertility is nubility.
 Historical shift
The age at which puberty occurs has dropped significantly
since the 1840s.
Researchers refer to this drop as the 'secular trend'.
From 1840 through 1950, in each decade there was a drop
of four months in the average age of menarche among
Western European female samples. In Norway, girls born in
1840 had their menarche at average 17 years. In France in
1840 the average was 15.3 years. In UK the 1840 average
was 16.5 years for girls. In Japan the decline happened later
and was then more rapid: from 1945 to 1975 in Japan there
was a drop of 11 months per decade.
Whincup PH, Gilg JA, Odoki K, Taylor SJC, Cook DG (2001)-Age of menarche in
contemporary British teenagers: survey of girls born between 1982 and 1986. BMJ
322: 1095–1096.
 Factors influencing P onset (1)
Genetic influence & environmental factors: The genetic
association of timing is strongest between mothers and daughters. The
specific genes affecting timing are not defined yet. Among the
candidates is an androgen receptor gene*
* Comings DE, Muhleman D, Johnson JP, MacMurray JP (2002)- Parent-
daughter transmission of the androgen receptor gene as an explanation of the effect of
father absence on age of menarche. Child Dev 73 (4): 1046–51
Hormones and steroids. There is theoretical concern, and animal
evidence, that environmental hormones & chemicals may affect aspects of
prenatal or postnatal sexual development in humans.
Large amounts of incompletely metabolized estrogens and progestogens from
pharmaceutical products are excreted into the sewage systems of large cities, and
are sometimes detectable in the environment.
Significant exposure of a child to hormones or other substances that activate
Estrogen/or Androgen receptors could produce some or all of the changes of
puberty. polychlorinated biphenyl ; bisphenol A
 Factors influencing P onset (2)
Nutritional influence. Girls are especially sensitive to nutritional
regulation because they must contribute all of the nutritional support to
a growing fetus. Surplus calories (beyond growth and activity
requirements) are reflected in the amount of body fat, which signals to
the brain the availability of resources for initiation of puberty &
fertility.
- Recent worldwide increased consumption of animal protein, other changes in
nutrition, and increases in childhood obesity have resulted in falling ages of puberty,
mainly in those populations with the higher previous ages.

- Although available dietary energy (simple calories) is the most important dietary
influence on timing of puberty, quality of the diet plays a role. Lower protein intakes
and higher dietary fiber intakes, as occur with typical vegetarian, are associated with
later onset and slower progression of female puberty.
Obesity influence & exercise: effects on timing
Physical and mental illness
Stress and social factors: small influences on timing. Family role
 Differences between male & female puberty
Two of the most significant differences between
puberty in girls & puberty in boys are:
- the age at which it begins, and
- the major sex steroids involved.
Although there is a wide range of normal ages, on average,
girls begin the process of puberty about 1– 2 years earlier than
boys (with average ages of 9 to 14 for girls and 10 to 17 for
boys), and reach completion in a shorter time, with girls usually
having completed puberty by age 17.
Girls attain adult height and reproductive maturity about 4
years after the first physical changes of puberty appear.
In contrast, boys accelerate more slowly but continue to
grow for about 6 years after the first visible pubertal changes.
 Female development at adolescence/puberty

 The hormone that dominates female development

is estradiol (E2)
 While estradiol promotes growth of breasts and
uterus, it is also the principal hormone driving the
pubertal growth spurt and epiphyseal maturation and
closure.
 E2 levels rise earlier and reach higher levels
in women than in men
 In males, testosterone is the principal sex steroid.
 While testosterone produces all the male changes
characterized as virilization, a substantial product of
testosterone metabolism in males is E2, though levels rise
later and more slowly than in girls.
 The male growth spurt also begins later, accelerates more
slowly, and lasts longer before the epiphyses fuse.
 Although boys are 2 cm shorter than girls before puberty
begins, adult men are on average about 13 cm (5.2 inches) taller
than women.
 Most of this sex difference in adult heights is
attributable to a later onset of the growth spurt and a
slower progression to completion, a direct result of the
later rise and lower adult male levels of estradiol.
 Hormonal changes in girls (1)
As the amplitude of LH pulses increases, the theca
cells of the ovaries begin to produce testosterone and
smaller amounts of progesterone. Much of the
testosterone moves into nearby granulosa cells.
Smaller increases of FSH induce an increase in the aromatase
activity of these granulosa cells, which converts most of the
testosterone to E2 for secretion into the circulation.
Rising levels of E2 produce the characteristic estrogenic
body changes of female puberty:
- growth spurt, acceleration of bone maturation and closure,
increased fat composition,
- breast growth,
- growth of the uterus, increased thickness of the endometrium
and the vaginal mucosa, and widening of the lower pelvis.
 Hormonal changes in girls (2)
As the E2 levels gradually rise & the other
autoamplification processes occur, a point of maturation is
reached when the feedback sensitivity of the hypothalamic
"gonadostat" becomes positive.
This attainment of positive feedback is the hallmark of
female sexual maturity, as it allows the mid cycle LH
surge necessary for ovulation.
Levels of adrenal androgens & testosterone also
increase during puberty, producing the typical androgenic
changes of female puberty: pubic hair, other androgenic hair as
outlined above, body odor, acne.
 Growth hormone levels rise steadily throughout puberty.
 IGF-1 levels rise and then decline as puberty ends.
 Growth finishes and adult height is attained as the estradiol
levels complete closure of the epiphyses.
 What is menopause (M)?
M.a period in all women’s life without menses for 12
consecutive months, when the body undergoes many other
changes: heart & vessels, bones, brain, muscle, skin, breasts,
& reproductive organs
The WHO defines M. as the permanent cessation of
menstruation resulting from the loss of ovarian follicular
activity
Gradually declining estrogen levels begin as early as in
the 30’s – this is referred to as peri-menopause.
M. usually occurs around age 51.2 yrs (range: 39 – 59)
when the ovaries stop producing estrogen, or surgically at
any age when the ovaries are removed.
 The changes of ovarian reserve during aging and the involvement of these
quantitative changes on some ovarian and hypothalamo- pituitary endocrine
factors: Soules M, et al, 1998

There is a theory on
the interactions FSH- activin,
which drives
to a loop of self-control,
that accelerates follicles
growth and development,
with jeopardizing the
maturation and meiosis in
oocytes

Erickson GF, 2000

 Stages of reproductive aging
Utian W, American Workshop on Reproductive Aging, 2001
Menopausal Transition – It starts with the variation of cycles
duration and ends with the last period (which is recognized only after 12
months of amenorrhoea)
Stage -2 (early) is characterized by menstrual cycles with variable length
(with >7 days difference to the length of a normal cycle, between 21 and
35 days)
Stage -1 (late) is characterized by missing menses during 2 consecutive
cycles or amenorrhea ≥ 60 days, period when the woman experiences hot
flushes. It is lasting 4 years average (range 0 and 10 yrs).
Perimenopause - " near menopause", starts from the stage -2 of
menopausal transition and ends at 12 months after last menstruation
M. – a retrospective evaluation after 12 months of permanent menses
cessation, reflecting complete/near complete depletion of ovarian
follicles/some follicles with weak FSH responsiveness may persist
 Menopause, Perimenopause & Postmenopause:
Definitions, Terms & Concepts
Kenemans Peter, 2007- OBGYN. net Menopause & Perimenopause
M. and last ovulatory bleeding are not identical in many cases.
Although a menopause age of 57 and over is regularly reported, the age
of the oldest woman becoming pregnant in a natural way ever reported
was 56 years - Guiness Book of Records
M. occurring before the age of 40 is called precocious or premature
M. Today, the term premature ovarian failure (POF) is also used.
The incidence of premature menopause is ~ 1%.
The perimenopause can be defined as the period of time around
the menopause in which marked menstrual cycle changes occur, often
in conjunction with vasomotor symptoms and in which no period of 12
consecutive months of amenorrhea has yet occurred. The median length
of the perimenopause is 4 to 5 years (range: 1 - 9 yrs).
 Menopause, Perimenopause & Postmenopause:
Definitions, Terms & Concepts
Kenemans Peter, 2007-
OBGYN. net Menopause & Perimenopause

The postmenopause: period of life after the M.

Increasingly, the term menopause is used in a different sense to its
original meaning. The term menopause then refers to the total
postmenopausal period and thus is synonymous to the term
postmenopause.
Early menopause is a term sometimes used to denote the first few
years directly after menopause, in which still considerable,
endogenous oestradiol activity can be present.
Late menopause is the period thereafter
 Pathophysiology: Hormons (3)

The increase of
FSH (≥ 35 ng/ml ) & LH,
the decrease of
estradiol & inhibine
are usually used for the diagnosis
of Menopause
 Symptoms of Menopause

• Irregular periods • Mood swings

• Hot flashes • Vaginal dryness
• Sleeplessness • Urinary incontinence (urge)
• Dry skin • Depression
• Tachycardia • Osteoporosis+ joints pains
• Loss of libido • Hair loss
In the twenty-first century it will not be
uncommon for women to live over one-third of
their years after menopause.
Mortality and morbidity from CHD in men and women during
26yrs of follow-up in Framingham Studies.
Am Heart J, 1986

 CHD is the first cause of

death world-wide.
 Atherosclerosis is the
explanation of women’s higher
risk after 45 yrs vs men , being
similar at 75 yrs for both
genders
 It had induced 32% of all
women’s death vs 26.9% in
men- in 2001.
Progressive evolution of atherosclerosis
(5 stages)
 Incidence of cardiovascular disease and deaths from other causes per 1000 person years by age
and sex in the derivation cohort of 2 343 759 patients.

Risk Score for Death by

cardio-vascular diseases and
non- cardio-vascular in
England and Wells
Hippisley-Cox J, et al: BMJ 2010;341

©2010 by British Medical Journal Publishing Group

 Perimenopausal Women

As women approach menopause, cycles shorten

and often become intermittently anovulatory.
These changes are the result of a decline in the
number of ovarian follicles and in the estradiol
level.
As follicles decrease in number, the level of FSH
needed to stimulate ovulation increases.
 Steroidogenesis at Menopause (1)

Estrogens: After M estradiol is constant: < 40 pg/ml –

Vermeulen A, Verdonck L, 1978
ovarian secretion of E2 being absent
Adashi EY, 1994
similar to that of premenopausal ooforectomized women
 E2 (< 40pg/ml) & E1 (100pg/ml) from
postmenopause are due to tissues abilities (adipos, muscular,
liver, bone marrow, brain, hair follicles) to aromatize the
ovarian and adrenals androgens : the conversion of
androstendion - 85% (adrenal) & 15%( ovarian);
 the conversion of E1 (after menopause the level of E1 is
higher and is similar to those early follicular phase from
premenopause); average synthesis is for E2 = 12g/24h, without
nictemeral rithm
 Steroidogenesis at Menopause (2)

Progesterone: values with cu 30% lower that those of

follicular phase of younger women, the source being the adrenals,
because the ageing ovaries do not have follicles that can ovulate
Androgens:  through the ovarian & adrenals
components, generating the state named "adrenopause", with
increased global ratio androgens/estrogens.
The ovaries are secreting 20% of Androstendion & 40% of
Testosterone in postmenopause becasue the stimulation of stromal
cells by excessive LH .
Androstendion: reduced at 1/2 in menopause, with average
production of 1.5 mg /24h & circadian rithm, peak at 8.00 a.m.
and p.m, & nadir at 3.00 & 4.00 a.m.
 Steroidogenesis at Menopause (3)

Testosterone: less changes (sometimes increased vs

premenopause), with rate of 150 g/24 h & nictemeral rithm
: peak at 8.00 a.m and nadir at 4.00 p.m; becomes from
circulanting androstendion, with ovariană origin (cells from
the ovarian hill and stromal luteinized cells, stimulated by
gonadotrops)
Adrenal Androgens - DHA and DHAS are reduced
with 60% and 80%, respectively
DHA has circadian rithm, but DHAS does not have
ADRENOPAUSE
 Management

 Timing of mHT from menopausal transition

 “Window of opportunity”- the first 5 yrs after M
 Individualized menopausal hormone therapy
 Minimum amount of steroids
 Treatment for vasomotor syndrome, insomnia, vaginal
atrophy (genito-urinary syndrome) (estriol, DHEA)
 Prevention of osteoporosis, reduction of fractures
 Duration: 10 yrs, with yearly breast & genital check
Recommendations of IMS- 2016; NAMS, 2016; EMAS, 2017

When premature/precocious Menopause,

TH is imposed to be administered up to the age of
natural Menopause
 Romero M: Adv Nurse Pract. 2002
Bioidentical hormone replacement therapy.
Customising care for peri-menopausal & menopausal
women.
Emphasis on individualized doses
rather than "one dose fits all" approach of
conventional hormone replacement therapy
TIMING
Dose, route (oral, non-oral) & duration of
administration/use
Type of regimen: Estrogen ± Progestin/progesterone
sequential, continuous –combined
 Contraindications of menopausalTH

 Sângerări vaginale neexplicate

 Boli hepatice active
 Tromboze active/ istoric de tromboze venoase
profunde sau pulmonare
 Boala cardio vasculară diagnosticată
 Lupus eritematos diseminat
 Femei cu antecedente de cancer mamar
 Femei cu cancer mamar sau endometru
 Melanom malign- istoric, actual
 Contraindications of menopausalTH
Terapia hormonală la menopauză interferă cu
patologia cardiovasculară, hepatică, creşte riscul
neoplaziilor mamare
 Boli active ale veziculei biliare
 Istoric de migrene
 Creşterea trigliceridelor serice
 Istoric de cancer de sân (mai mult decât un caz la rude grad
I)
 Istoric de fibroame
 Hiperplazie atipică ductală mamară
The decision tree
for HRT
Nov 2010, EMAS
 Kronos Early Estrogen Prevention Study
(2008-2012) Results (1) : Gives New Insight Into HT
Primary Study Assessment of atherosclerosis progression
727 participants:randomized into 3
groups.  Yearly ultrasound imaging studies on all
participants to estimate thickening of the walls of
- I. 0.45 mg/d Premarin, (o-CEE)
the common carotid arteries.
lower than the 0.625 mg/d used in the
WHI  Coronary artery calcium (CAC- a marker for
- II. 50 µg/d trsd estradiol (t-E2) atherosclerotic plaque) was also assessed using
high-resolution CAT scans before and at the end
via a Climara patch,
of the study
- III. placebo
Women on active E received 200 mg of
micronized progesterone (Prometrium) x The carotid ultrasound studies
12 ds/ month, and women on dual showed similar rates of progression of arterial
placebos were given identical placebo wall thickness in all 3 treatment groups
capsules during the same time period. over the 4 years of study.
64% of the women (466) completed all These changes were generally small,
4 yrs of the trial (compared to 50-60% limiting the statistical power
compliance in the WHI) and another to detect any differences among the groups.
16% (118 women) discontinued the
study medication but continued to be
followed throughout the study.
 KEEPS Resultats (2)
Gives New Insight Into Hormone Therapy
Cognitive Study
All 662 women enrolled in the cognitive study were  However, no beneficial effects of
free of depression, dementia, or memory deficits at HT on cognition were seen either.
baseline. They were given a comprehensive battery  Compared to placebo, women
of tests measuring cognition and mood at the
beginning of the study and in months 12, 18, 36, assigned to the o-CEE group
and 48. improved significantly on measures
of depression-dejection & anxiety-
Results revealed: unlike prior studies involving tension.
HT for older postmenopausal women, such as the
Women’s Health Initiative Memory Study  The o-CEE group also showed a
(WHIMS), the WHI Study of Cognition and trend in improvement on measures
Aging (WHISCA), and the Heart and of anger-hostility & memory recall
Estrogen/Progestin Replacement Study (HERS), of printed material.
administration of o-CEE and t-E2 to  The t-E2 group had a trend toward
recently menopausal women did not adverse performance in memory of
create any detectible adverse effects
past events and their severity.
either on domain-specific or general
measures (ie, 3MSE*) of cognition.
*3MSE (mental state examination)
 Estrogen /Hormone Replacement Therapy (HRT)
HRT has
that appear to be
antiinflammatory + converted to
vasoprotective proinflammatory
effects and
when administered to vasotoxic effects
young women in older subjects,
or particularly those that
have been hormone
experimental animals → free for long periods

Clinical studies have raised many important questions about

the vascular effects of estrogen that cannot easily be
answered in human subjects
 Progesterone/ Progestins in HRT
To distinguish between
bio-identical or non bio-identical progesterone
- P given alone does not It is important to
adversely affect vascular
function in postmenopausal distinguish the real
women progesterone from its
- preventive role against substitutes: the
coronary artery spasm induced
heart attaches progesterone
Kamazin M, et al, 1979 substitutes
- a fast acting calcium blocker (progestins) does
- natural progesterone at
physiological dose does not become a risk factor
interfere with NO dependent in many ways, including
dilatation but not limited to
Mather KJ, et al, 2000
- can induce NO production
coronary artery spasm