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Файл:Physiology of the development of the reproductive system of girls. Standards for determining physical and sexual maturity. Study aid
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is desquamation phase, accompanied by menstrual-like discharge from the
genital slit.
At the same time, the scarcity and short duration of blood discharges usually
do not require medical intervention. Prolactinemia with prolactin levels sometimes
more than 1 000 mlU/l takes place up to two months. Neonatal hyperprolactinemia
combined with hypersecretion of GH and remaining estrogenic influences, causes
enlargement and engorgement of the mammal glands (3–8th day), sometimes even
with colostrums from the nipples.
Hormonal crises occur only in healthy children; they pass away soon, and do
not require treatment. Specified features are individual, and, with the exception of
enlargement and engorgement of the mammal glands, they disappear in most girls by
10th and in some girls (15–20 %) by 28th day of life. However, 1.5–2 % of infants
have enlargement of mammal glands up to 3–6, and sometimes 8 months of life.
A girl is born with clearly differentiated external genital organs of female type.
The clitoris is relatively large. The vestibular glands do not function. Variability in
size, shape (annular, lunate, labial) and type of hymenal membrane and hymenal
foramen (or foramina) attract attention.
The vagina is located parallel to vertical axis. Its lines can be from 25 to
35 mm. The vaults, especially the rare ones in already formed. Abundant folding of
the walls is determined, the muscular layer of which is quite clearly expressed. The
mucous membrane of newborn girl vagina consists of several layers of squamous
epithelium of intermediate type. However, with the influence of estrogens and
progesterone, which have come to the fetus from uteroplacental blood flow,
epithelium cells are able to produce glycogen, thereby supporting the vital activity of
lactic acid bacteria. By the end of the first month of life, girl`s thin and easily
vulnerable vagina epithelium is represented only by basal and parabasal cells.
Reaction of vaginal contents becomes alkaline, pH rises up to 7.0–8.0. Lactobacilli
disappear.
The uterus in newborn girl is located in abdominal cavity. The area of external
pharynx is located not below the line, corresponding diagonal conjugate. Uterus
length is 30 mm on average. Uterus body has a lenticular shape, the bottom is slightly
concave (saddle-shaped). The ratio of the length of cervix and uterus body is 3/1.
Body and cervix almost do not form an angle between themselves. The uterus is in
anterversion.
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Not only endocervix, but also the endometrium forms a large number of folds.
The internal pharynx from point (in fetuses) turns into a slit-like (in a newborn). In
area of external os, the junction of cervical canal is often located on ectocervix. The
cervical canal is filled with thick mucus that can enter the vagina.
By the moment of birth, a girl`s fallopian tubes reach an average of 35 mm.
The tubes are twisted due to the relatively short wide ligament. The muscular layers
of the tube wall are well developed. Tubes are passable throughout. Even with
normal intrauterine development, asymmetry of the fallopian tubes is observed: the
right tube is 5 mm usually.
The ovaries of newborn girls are cylindrical, rarely prismatic formations with a
length of 10 to 20 mm, a width of 5 mm and thickness from 1 to 4 mm. The ovaries
have a smooth, sometimes convex surface due to maturing follicles and are located
on the border of small pelvis and abdominal cavity. The structure of ovaries in this
period of life is represented by cortical layer containing from 1 to 2 million
primordial follicles. The medulla is poorly expressed. In girls, from birth and to
12 months of life, the size of separate follicles sometimes reaches 15 mm, and follical
fluid contains steroid hormones and proteins. Along with primordial and maturing,
many follicles in state of atresia can be found.
With the end of neonatal period, the size of internal genital decreased. The
uterus during echographic examination is determined in the form of a tube 2–2.4 cm
long, located under the entrance to small pelvis. The endometrium becomes thin and
is not visualized.
By 2–4 months of life, the secretion of gonadotropic hormone returns to the
level, which was in fetus the day before birth.
1.3. CHILDHOOD PERIOD
The period of childhood lasts from 1 to 8 years and is divided into several
stages, which differ from each other by the predominant influence of different sex
hormones.
Early childhood, up to 3 years of age, is characterized by active transformation
of child`s adrenal glands. At 2 years after birth, the embryonic cortex completely
disappears, and one year later, mature adrenal cortex finally differentiates. There are
three areas here, glomerular, fascicular, and reticular. The outer glomerular area
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become the main size for aldosterone synthesis. The middle fascicular are has all
enzymes necessary for the synthesis of cortisol and androgens. The third area is
reticular one, it is necessary for cortisol synthesis and formation of androgenic
metabolites: dehydroepiandrosterone (DEA) and androstenedione.
The period of middle childhood is characterized by formation of mature
adrenal cortex. The secretion of cortisol and aldosterone increases, it allows child`s
body to react adequately to life-threatening effects. Cortisol inhibits HnRH secretion,
corticotrophin-releasing hormone, inhibits cell proliferation by suppressing the
production of growth factors, interleukins and cytokines. Suppression of
corticotropin-releasing hormone by cortisol leads to deceleration in formation of
ACTH precursor, lipotropin, melanocyte-stimulating hormone and endorphins. The
latter, on background of low level of estrogens, support weak sensitivity of
gonadotrophs to GnRH.
Average values of LH secrection in girls from 3 to 6 years are between 1.3 and
2.5 mlU/l, and FSH between 1.2 and 1.5 mlU/l. During this period of development,
girls may have short-time increase of FSH, LH and ACTH secretion. During sleep,
both the average content of LH (5 times) and amplitude of emissions (3 times)
increase. It is caused by the end of formation of architectronics of hypothalamus and
improvement of connections in hypothalamic-pituitary zone with target organs. But
chaotic and low-amplitude emissions of gonadotropins, primarily FSH, cannot
activate the ovaries.
In the ovaries, the processes of follicular atresia are actively continuing, and
the number of primordial follicles is double reduced compare to neonatal period. The
content of estradiol in blood plasma of girls during early and middle childhood varies
at a very low level (from 10 to 80 pmol/l). The ovaries are located high near small
pelvis walls, and their sizes vary from 8×6×5 mm to 13×11×15 mm.
In girls under 3 years of age, the uterus remains cylindrical shape, the cervix is
not clearly differentiated. The length of uterus, according to ultrasound, varies from
24 mm at the age up to 1 year, and 28 mm at the age of 3 years. By the age of three,
the bottom of the uterus descends to plane level of small pelvis. After 3 years the
uterus begin to enlarge from 28±1 mm at the age of 3 to 32±1 mm at the age of
5 years. The endometrium is not visible on echogram. An important specialty of
small pelvis topography in girls up to 6 years is location of uterus artery on 10–12 cm
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lateral to uterine ribs, as well as close contact of ureter with a middle part of cervix
and anterior wall of vagina.
In girls of 6–8 years old the content of androgenic metabolites of
steroidogenesis, DHEA and its sulfate, and then androstenedion, begins to incrase. It
occurs due to increase in proportion of reticular zone in structure of permanent
adrenal cortex. This period is called “adrenarche”, and it usually occurs in late
childhood period. By 8–10 years, gonadotropin increases, which which trigger the
process of prepuberty and puberty. It should be noted that aderenarche is not
manifested by sexual hair growth, but only creates conditions for hair growth, first on
the pubis, and then in axillary areas.
During this period of life, there is a short-term so-called children`s growth
spurt, which is not determined on standard growth rate curve, but it can be noticed at
the regular registration of growth in one and the same child. The increase in girl`s
height is directly connected with age-related mass of her body. It happens due to
anabolic action of androgenic steroids, which stimulate lipogenesis, increase muscle
mass and increase muscle strength.
Body weight in girls enlarge mainly due to fat accumulation, which is
manifested mainly in girls of 8–9 years by enlargement of circumference of the lower
half of pelvis. Due to growth of adipose tissue, the external genital organs girl
become more convex-shaped and mature look. Adipose tissue accumulation
contributes to activation of extragrandular conversion of androstenedione to estrone,
which leads to increased in the content of total estrogens to a level that can provide
increase in sensitivity of adenohypophysis gonadotrophs to impulse secretion of
GnRH. Estrogens and aromatized androgens have a strong stimulating effect on
development of neuroendocrine connections in the hypothalamus. All this plays
a decisive role in final formation of full-fledge synaptic connections of
neurosecretory neurons, releasing GnRH, with other cells of hypothalamus and fibers
of brain pathways.
An increase in androgen-producing activity in girls of 6–8 age coincides with
increase in total ovary volume due to increase in the mass of stromal and
thecacellular components.
Vagina and internal sex organs slightly change during the period of adrenarche.
Cleansing of vagina happens due to phagocytic function of macrophages and
polymorphonuclear leukocytes. The specialties in external sex organs structure are
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compensation for decrease of internal security. Vulvar ring gapes because of thin
semilunar or annular rigid hymen, but its location in the deep navicular fossa and
delimination from the anus by high posterior commissure normally prevents massive
colonization of lower genital tract by exogenous microflora. The microscopic picture
of vaginal discharge is characterized by the presence of free epithelium cells of
parabasal and intermediate layer with signs of cytolysis, strands of mucus in the
absence of leukocyte reaction (leukocytes are absent or represented by single cells in
the field of view). Among the isolated microorganisms, facultative anaerobs prevail,
represented by staphylococci, streptococci and corynebacteria, much less often, by
enterococci and Escherichia coli.
1.4. PREPUBERTAL PERIOD
The peculiarities of prepubertal period (from 8 years to menarche) is
unchanging concentration of tropic hormones of pituitary gland (LH, FSH, TSH,
ACTH) and prolactin, but despite this, a half of children of both gender have impulse
LH secretion within the day, especially at night. In 1–2 years before menarche,
gonadotropin bursts during sleep, and then in daytime happens more often, but
nighttime bursts continue to predominate over daytime impulses in amplitude.
In prepubertal period, transient hyperplasia of thyroid gland is observed in girls
of prepubertal age, there is a slight increase in secretion of thyroxine and
triiodothyronine.
Increased ovary activity is confirmed by increase in concentration of estradiol
to 100 (68–148) pmol/l. During prepubertal period the ovaries reach size 30–
35×20×15 mm. The follicles on different stages of maturation appear in cortical level.
Together with primordial follicles, the number of which decreases to 400–
300 thousand, cavity follicles with diameter from 10 to 30 mm, atrezable follicles and
fibrous bodies are found.
The average length of uterus before menarche increased from 3,55±0,06 to
4,9±0,16 cm, width — from 1,68±0,06 to 2,03±0,13 cm and anteroposterior size from
1,08±0,06 to 1,5±0,12 cm. The ratio between the length of body and cervix becomes
equal to 1. Reflection from endometrium in girls under 10 years before menarche —
0,2–0,3 cm.
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Due to initial hormonal influences, vulvar ring shifts outward, and the hymen
becomes elastic and wrinkled. Large labia are enlarged due to accumulating adipose
tissue, they thicken and close the genital gap. Thickness of vagina epithelium layer is
significantly increased. A glycogen appears in multilayer epithelium. There is gradual
replacement of coccal flora in vagina to coccal-bacillary ones. Common microbial
number increases to 105–106 CFU/ml. Only by 9.5–10.5 years, when concentration of
estradiol reaches 100 nmol/l, vagina is mainly populated by lactobacilli. By the end
of prepubertal period, i.e. in the year of menarche, karyopyknotic index reached
30 %, and eosinophilic index reaches 20 %. Neutral-acid reaction of the vaginal
contents gradually turns into a slightly acidic one.
An increase in estradiol concentration against the background of activation of
thyroxine by thyroid gland leads to an increase in the amplitude and more frequen
impulses of growth hormone secretion. In turn, increase of growth hormone secretion
mediates the effect of sex steroids, mainly estrogens, on pubertal acceleration of
growth and appearance of hairiness. Growth hormones together with prolactin,
thyroxin and sex hormones have a pronounced mammotropic effect, stimulating the
growth of the ducts and stromal components of mammal glands. On average, within
2–3 years (from 9 to menarche) mammal glands go through the main development
stages.
One more specialty of prepubertal period is the presence of growth spurt at the
age of 11–12 years, when increase of body length takes 8–11 cm per year, and the
height reaches 140–167 cm depending on region where the girl lives. More fast
growth of tubular bones compared to spine is observed, this causes the fact that girls
become “lanky” by the age of menarche.
Skeleton growth stops after the “jump”, which is confirmed by the absence of
maturation index change. The latter, as known, represents the ratio of upper
(difference between the pubic arch and the crown of the head) to the lower segment
of body (distance between lunar arc and soles of feet).
The critical age for weight gain is 11–12 year of life. Increase of this indicator
is observed not earlier than in 6–12 months after maximum enlarge of body length.
This period coincides with pubic hair growth and mammal gland enlargement up to
3rd stage (by Tanner).
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1.5. MODERN VIEW ON THE TRIGGERS OF MENARCHE
Over the past 100 years there has been a decline in average age for menarche.
So for example, in Europe and Northern America since early XIX this age
corresponded to 16–17 years, and in the second half of XX it was already 13. This
tendency is connected with improvement of social and economical conditions that
occurred during this period. This parameter has wide fluctuations depending on the
ethnic group.
The age of beginning of puberty and mechanisms that trigger this process, have
multifactorial dependence. Now there is no single point of view on this issue.
Today, hypothalamic-pituitary-gonadal system is considered by scientists as
the main evolutionarily formed mechanism of positive and negative connection in
regulation of gamete maturation process. This system is “switched off” in fetus, but it
plays an important regulatory role in postnatal period, beginning with puberty period.
It is already known that it performs its function through the hormones gonadotropin
(GH), gonadotropin-relesing hormone (GnRH), follicle-stimulating (FSH-β),
luteinizing (LH-β) hormones, and their receptors (GnRHR, FSHR, LHR).
Many genes regulating puberty and gonade functions have been identified.
According to the data of American researches, a new gen GRP54 was discovered for
the first time, this gen triggers and later is responsible for puberty period and
maturation. Activation of this particular gene, according to scientists, causes so called
hormone explosion — the main active principle in this process. And mutations in this
gene lead to delay in sexual development, as scientists from Massachusetts General
Hospital in Boston believes.
Additional regulators of hypothalamus-pituitary system (Fig 1) have also been
established: protein growth factor (PGF), kisspeptin (KISS1), kisspeptin-receptor
(KISS1R (GPR54)) and anosmin1 (gen KAL1, Kalman syndrome). The latter, in
particular, violates neuron migration, which are responsible for GnRH synthesis and
odor recognition. Kiss-dependent signaling is the central mechanism for regulation of
GnRH synthesis during steroid production. Its uncoupling due to mutation of coding
genes leads to violation of portioned (pulse) delivery of GnRH: loss of KISS1R
function is accompanied with decreased in regulation of GnRH production and
infertility, hyper activation — with premature puberty. Thus, it was shown that this way is
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primary transmitter between internal and external signals of microenvironment, critically
necessary for adequate regulation of neuroendocrine reproductive connection.
It also was found out those KiSS-1 neurons in hypothalamus act as sensors of
energy balance. Due to direct connection of KiSS-1 neurons with GnRH neurons,
effect of metabolic products (“metabolite hormones”) changes the activity of the
second ones and, consequently, of whole gonadotropic axis. Thus, through a change
in metabolic state of the body, it is possible to increase or decrease the production of
an additional amount of hormones endogenously and thereby stimulating or
suppression of sexual function.
Figure 1. Scheme of regulation of hypothalamus-pituitary system with participation
of the Kiss-dependent signaling pathway (kisspeptin (KISS1), kisspeptin-receptor
(KISS1R (GPR54) and anosmin1(gen KAL1, Kalman syndrome)
In pubertal period, γ-amine-oil acid (GAOA) also plays a big role, which in the
given age period has high concentration and inhibits an allocation process of
gonadotropine-releasing hormone.
The mechanisms that regulate the duration of beginning of puberty capture
particular interest of researchers for several decades, but still there is no specific and
proven factors, which could shed a light on this question.
The scientists consider two main trigger mechanisms. The first one, is the most
researched, suggests that the signal for awakening of the pulsed regime of GnRH
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release is achievement of a certain maturation of somatic system. According to this
hypothesis, the brain receives this information in the form of a signal tracked in CNS.
It is known that for normal sexual development of reproductive system,
a certain ratio of adipose tissue in body is necessary. So, for girls with excessive body
mass, earlier puberty is more typical than that of their peers.
Recently, interest to this hypothesis was resumed due to discovery of protein
produced by adipocytes, leptin, which regulates food behavior and body mass. In its
publications (1998) it notes that leptin content in blood can be a signal indicating
readiness of body to perform reproductive functions and the presence of sufficient
reserves of nutrients necessary for its normal flow.
But there are also research results, according to which women with low leptin
content on background of lipodystrophy had normal terms of development of
reproductive system. These data convincingly prove that leptin action, although is
compulsory for puberty occurrence, but nevertheless is not determinant.
Another somatic factor that triggers menarche process is bone age. Correlation
between menarche onset and bone age was discovered in several researches.
Confirmation of this theory is the fact that the children with constitutional growth
delay and isolated hormone growth have menarche at later chronological age.
Active growth of bone tissue begins when testosterone, aromatized to estradiol,
increases STG content (somatotropic hormone), whichinduces a parallel increase in
concentration of somatomedin 1 (insulin-like growth factor 1). Somatomedin 1 acts
as a powerful anabolic hormone, mediating many metabolic functions of STG,
including bone formation. In normal conditions, STG stimulates somatomedin
1 synthesis, and somatomedin 1, in turn, inhibits STG release by mechanism of
negative response. Somatic growth during puberty is cause by common action of sex
hormones, STG and somatomedin 1 (or somatomedin receptors) lead to dwarfism
even with sufficient concentration of sex hormones in plasma. It confirms that these
hormones play important role of the hormone data not only for somatic growth, but
also for start of puberty period.
One more theory of puberty triggering is the presence of insulin resitence in
adolescents. Thus, when examining 224 people in age from to 20 years, not suffering
from obesity (1998, Laron et al) discovered that insulin and C-peptid levels rise
sharply at puberty onset, although glucose levels remain unchanged. After puberty
onset, insulin level progressively decreases, reaching prepuberty values. These data
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confirm hypothesis that puberty is accompanied by physiological insulin resistance.
A number of scientists associate it with increase of growth hormone (GH)
concentration in plasma during puberty, which leads to violation of insulin action.
Thus, taking metmorfin during 3 years in girls with early puberty significantly
inhibits this process. All this allows to suggest that insulin resistance is an important
component in the process of sexual maturity formation.
According to the second scheme, the pubertal mechanism in initiated by
descending path, generating a signal directly from CNS.
The first phase of puberty period is characterized by maturation processes of
hypothalamic structures, a close synaptic connection is formed between cells,
secreting neutrotransmitters and liberins (RG-LH, somatolyberin, corticoliberin,
thyrolieberin). RG-H secretion acquires rhythmic character, the circadian (daily)
rhythms of RG-LH emissions is established, actually firstly these emissions happen
during night sleep. Under the influence of increased RG-LH emission, gonadotropin
synthesis increases, and emissions also become rhythmic. The number of receptors to
sex steroids in cells of all organs of reproductive system, including hypothalamus and
pituitary. Their sensitivity to estradiol is changed because of it. The achievement of a
certain high level of estradiol in blood signal is a signal to powerful emission of
gonadotropins, which finishes maturation of follicle and egg cell emission.
Despite the fact that the basal secretion of gonadotropic hormones and
prolactin in pubertal period in girls with menarche approaches to the level of these
hormones in women of reproductive age, during 10–18 months after menarche
anovulatory menstrual cycles often reveal on background of regular menstruation. So,
if 50 % of 12–13-year-old-girls have anxulatory cycles, then in 14 years only each
third girl is recorded such cycles.
In the 2nd phase of pubertal period (15–18 years), a stable rhythm if RG-LH
secretion is established. Its emissions become more frequent and occur every 70–
100 minutes, once a hour on average. This rhythm was called circhoral (hour). It is
formed under the influence of cerebral structures and it is genetically explained,
circhoral type of discharge of RG-LH is the basis of control of gonadotropic function
of adenogiposis. In response to the rhythmic release of RG-LH, the release of LH and
FSH increases, which leads to increase of E2 synthesis in the ovaries. There is a
moment when, along with mechanism of response, which existed in the period of
antenatal development, mechanism of positive response is formed: achievement of a
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