KIA Semester III.

PENGANTAR

FISIOLOGI REPRODUKSI

Kuliah 1

Rahmatina B. Herman

Bagian Fisiologi

Reproduction

Reproduction is process

to maintain

continuation of species

by which

-

new individuals

of a species are produced

-

genetic material

is passed from generation

to generation

Cell division in a multicellular organism is

necessary for growth and it involves passing of

genetic material from parent cells to daughter

cells

The Reproductive System

does not contribute to homeostasis

is not essential for survival of an individual

But still plays a i porta t i a perso ’s life,

e.g. the manner:

- in which people relate as sexual beings

contributes in significant ways to

psychosocial behavior

- how people

view themselves

The Reprodu tive Syste …..

Reproductive function also has a profound

effect on society:

- universal organization of societies into

family units provide a stable environment

that is

conducive for perpetuating

our

species

- on other hand,

population explosion

and its

resultant drain on dwindling resources

have led to worldwide concern with means

by which reproduction can be limited

The Reprodu tive Syste …..

Reproductive capability depends on

intricate

relationship among hypothalamus, anterior

pituitary, reproductive organs, and target cells

of sex hormones

These relationship employ many of

regulatory

mechanisms

used by other body systems for

maintaining homeostasis, such as

The Reprodu tive Syste …..

Sexual behavior and attitudes are deeply

influenced by emotional factors and

socio-cultural mores of the society in which the

individual lives

However, Reproductive Physiology will

concentrate on basic sexual and reproductive

functions that are under nervous and hormonal

control,

and will not examine physiological and

social ramifications of sexual behavior

The Reprodu tive Syste …..

The organ of male and female may be grouped

by function

Testes and ovaries (gonads), function in

production of gametes: sperm and ova

Gonads also secrete hormones

The ducts of reproductive systems transport,

receive, and store gametes

Accessory sex glands produce materials that

support gametes

The Reproductive System

…..

In females, the breasts are also considered

accessory reproductive organs

The externally visible portions of reproductive

system are known as external genitalia

The production of gametes and fluid, and their

discharge into ducts classify the gonads as

exocrine glands

Whereas the production of hormones classify

the gonads as endocrine glands

Secondary Sexual Characteristic

Secondary sexual characteristic are many external

characteristics

not directly involved in

reproduction

That

distinguish male and female

Development and maintenance governed by

testosterone in males and estrogen in females

Progesterone has no influence on secondary

sexual characteristic

Axillary and pubic hair growth is not secondary

sexual characteristic

Secondary Sexual Characteristic

..…

In some species, secondary sexual

characteristic are great importance in courting

a d ati g ehavior e.g. to attra t fe ale’s

attention)

In humans, attraction the opposite sex not only

influenced by secondary sexual characteristic

but also

strongly affected by the complexities

of human society and cultural behavior

Overview of Functions and Organs

of Male Reproductive System

The essential reproductive functions of

male

are:

1. Production

of sperm (spermatogenesis) by

testes (in skin-covered sac: scrotum)

2. Delivery

of sperm to female

–

semen by

- male reproductive tract: epididymis, vas

deferens, ejaculatory duct

- urethra (in penis)

3. Male

accessory

sex glands: providing bulk of

semen: seminal vesicle, prostate,

Overview of Functions and Organs

of Female Reproductive System

Female

’s role i reprodu tio is ore o pli ated:

1. Production of ova (oogenesis) by ovaries

2. Reception of sperm: vagina-cervix

3. Reception of sperm and ovum to a common site for union (fertilization or conception): Fallopian tube

4. Maintenance of the developing fetus until it can survive in outside world (gestation or pregnancy), including formation of placenta (organ exchange between mother and fetus): uterus

5. Giving birth to the baby (parturition)

6. Nourishing the infant after birth by milk production (lactation): mammae

Overview of Functions and Organs

of Fe ale Reprodu tive Syste …..

Product of fertilization:

embryo

During first 2 months of intrauterine

development when tissue differentiation is

taking place

Developing living being is recognizable as

human:

fetus

-

no further tissue differentiation

Overview of Functions and Organs

of Fe ale Reprodu tive Syste …..

Female

reproductive tract consists of:

Ovaries

Oviduct s (Fallopian tubes)

- pick up ova on ovulation and serve as fertilization site Uterus, thick-walled hollow: responsible for

- maintaining fetus during development , and - expelling it at the end of pregnancy

Cervical canal

- small opening of cervix

- pathway for sperm to uterus then to oviduct - passageway for delivery of baby from uterus

Cervix

Overview of Functions and Organs

of Fe ale Reprodu tive Syste ……

Vagina

- expandable tube

- connects uterus to external environment

Vaginal opening

- located in perineal region

- between urethral opening and anal opening Hymen

- thin mucus membrane partially covering vaginal opening

• Labia minora and labia majora

- skin folds surrounding vaginal and urethral openings

• Clitoris

Sex Determination and Differentiation

Reproductive cells each contain a half set of

chromosomes

Gametogenesis is accomplished by

meiosis

The sex of and individual is determined by

combination of sex chromosomes

Sexual differentiation along male or female

lines depends on the presence/ absence of

masculinizing determinant

Parents with diploid (46 chr) somatic cells

Mother

Father

Meiotic division of germ cells

Meiotic division of germ cells

Haploid Ovum Haploid Sperm

Fertilization

Diploid fertilized Ovum

Mitosis

Ovum with X sex chromosome

Fertilized by

Sperm with Y sc Sperm with X sc

Embryo with XY sc Genetic sex Embryo with XX sc Sex-determining region

of Y chr (SRY) stimulates Production of H-Y antigen

In plasma membrane of undifferentiated gonad H-Y antigen directs

differentiation of gonads into testes

No Y chr, so no SRY and no H-Y antigen

With no H-Y antigen, undifferentiated gonads

develop into ovaries

Gonadal sex

Testosterone

Promotes development of undifferentiated external genitalia along male lines

(e.g. penis, scrotum)

Testes secrete hormone and factor

Phenotype sex Mullerian-inhibiting factor Dihydrotestosterone (DHT) Converted to Degeneration of Mullerian ducts Transforms Wolfian ducts into male reproductive tract

(e.g. epididymis, ductus deferens, ejaculatory duct,

Absence of testosterone

Undifferentiated external genitalia along female lines

(e.g. clitoris. labia)

Ovaries does not secrete hormone and factor

Phenotype sex

Absence of Mullerian- inhibiting factor Degeneration of

Wolfian ducts

Mullerian ducts develop Into female reproductive tract (e.g. oviducts, uterus)

Errors in Sexual Differentiation

Genetic sex and phenotype sex are usually

compatible

Occasionally, discrepancies occur

between genetic and anatomic sexes

Errors i Se ual Differe tiatio …..

1. If testes in

a genetic male

fail to properly

differentiate and secrete hormones, the result

is the development of an apparent anatomic

female in a genetic male, who, of course will

be sterile.

Similarly, genetic males whose target cells lack

receptors for testosterone are feminized, even

though their testes secrete testosterone

Errors i Se ual Differe tiatio …..

2. Testosterone acts on Wolfian ducts to convert

them into a male reproductive tract;

If testosterone derivative dihydrotestosterone

(DHT) that responsible for masculinization of

external genitalia because of genetic deficiency

of the enzyme which converts testosterone

into DHT, results in a genetic male with testes

and a male reproductive tract but with female

external genitalia

Errors i Se ual Differe tiatio …..

3. Adrenal gland normally secretes a weak

androgen, dehydroepiandrosterone in

insufficient quantities to masculinize females.

If, pathologically excessive secretion of this

hormone in a genetically female fetus during

critical developmental stages imposes

differentiation of reproductive tract and

genitalia along males lines

Errors i Se ual Differe tiatio …..

Sometimes, the discrepancies between genetic

sex and apparent sex are not recognized until

puberty, when discovery produces

psychologically traumatic gender identity crisis

For instance: a masculinized genetic female

with ovaries, but with male type external

genitalia may be reared as a boy until puberty.

When breast enlargement and lack of beard

growth signal an apparent problem

Errors i Se ual Differe tiatio …….

Less dramatic cases of inappropriate sex

differentiation often appear as sterility

problems

Therefore, important to diagnose any

problems in sexual differentiation in infancy. It

can be reinforced, if necessary, with surgical

and hormonal treatment, so that psychosexual

development can proceed as normally as

Tugas

1. Hubungan sistem limbik (limbic system)

dengan pengaturan fungsi seks

2. Hubungan kelenjar pineal (pineal body)

dengan pegaturan fungsi seks

DASAR-DASAR

BIOMOLEKULER

REPRODUKSI WANITA

Rahmatina B. Herman

Bagian Fisiologi

Fakultas Kedokteran Universitas Andalas

Sex Determination and Differentiation

Reproductive cells/gamete each contain a half

set of chromosomes (

haploid

)

Gametogenesis is accomplished by

meiosis

The sex of and individual is determined by

combination of sex chromosomes

Sexual differentiation along male or female

lines depends on the presence/absence of

Absence of testosterone

Undifferentiated external genitalia along female lines

(e.g. clitoris. labia)

Ovaries does not secrete hormone and factor

Phenotype sex

Absence of Mullerian- inhibiting factor

Degeneration of Wolfian ducts

Mullerian ducts develop Into female reproductive tract (e.g. oviducts, uterus)

Summary of 4 possible defects produced by maternal nondisjunction of sex chromosomes at the time of meiosis

The YO combination is believed to be lethal, the fetus dies in utero

/Ovarian agenesis/Turner syndrome

Female Reproductive System

Reproductive system of women shows regular cyclic

changes that may be regarded as periodic preparation for fertilization and pregnancy

In humans and primate, the cycle is a menstrual cycle and its conspicuous feature is periodic vaginal bleeding that

occurs with the shedding of uterine mucosa (menstruation)

In other mammal: the sexual cycle is called estrous cycle, no episodic vaginal bleeding occurs, but the underlying endocrine events are essentially similar

- in some species: ovulation occurs spontaneously - in other species: ovulation is induced by copulation

Ovaries

Primary female reproductive organs

Perform dual function:

- producing ova (oogenesis)

- secreting female sex hormones:

estrogen and progesterone which act together to: > promote fertilization of ovum

> prepare female reproductive system for pregnancy

Containing various levels of follicle

development

Histology of the ovary. The arrows indicate the sequence of developmental stages that occur as part of ovarian cycle

Oogenesis

Undergo numerous mitotic divisions

± 7 month after conception, fetal oogonia

cease dividing

From this point on, no new germ cells are

generated

Still in the fetus, all oogonia develop into

Primary Oocyte

Begin a first meiotic division by replicating their DNA However, they do not complete the division in the fetus

Accordingly, all the eggs present at birth are primary oocytes containing 46 chromosomes, each with two sister chromatids

Cells are said to be in a state meiotic arrest

State meiotic arrest continues until puberty and the onset of renewed activity in ovaries

Only primary oocytes destined for ovulation will ever complete the first meiotic division, for it occurs just before the egg is ovulated

Pri ary Oo yte…..

Each daughter cells receives 23 chromosomes, each with 2 chromatids

One of the two daughter cells, secondary oocytes retains virtually all cytoplasm (other is first polar body)

Thus, the primary oocytes:

- Already as large as the egg will be

- Passes on to be secondary oocyte half of its

chromosomes but almost all of its nutrient-rich cytoplasm

Secondary Oocyte

The second meiotic division occurs in a

fallopian tube after ovulation, but

only if the

secondary oocyte is fertilized (penetrated by a

sperm)

Daughter cells each receive 23 chromosomes,

each with a single chromatid

One of the two daughter cells, termed an ovum

retains

nearly all cytoplasm

(other is second

Final Result of Oogenesis

Net result of oogenesis is

that each primary oocyte

can produce only one

Summary of Oogenesis

Birth Puberty Oogonia Chromosomes Per cell Chromatids Per cell

46 2

2 46

23

23 1

Summary of

Ooge esis…..

Oogonia: mitotic divisions until ± 7 month after conception

Mitosis of oogo iu → primary oocyte

Meiosis of primary oocyte, but do not complete

(beginning of the 1st eioti divisio → eioti arrest

Primary oocyte at birth containing 46 chromosomes 1st meiotic division is completed just before ovulation

→ secondary oocyte

2nd meiotic division occurs in a fallopian tube after

ovulation, but only if the secondary oocyte is fertilized (penetrated by a sperm)

Comparison of Spermatogenesis and Oogenesis

Spermatogenesis

Three major stages:

1.

Mitotic proliferation

2.

Meiosis

3.

Packaging/ spermiogenesis

:

physically

reshaping/ remodeling

± 64 days, from spermatogonium to mature sperm

Up to

several hundred million sperm may reach

Follicle

From the time of birth, there are many

primordial

follicles

,

each containing 1 primary oocyte

Progression of some primordial follicles to

preantral and early antral stages occurs

- throughout infancy and childhood, and

- then during the entire menstrual cycle

Therefore, although most of follicles in ovaries are

still primordial, there are also always present

a

relatively constant few number of preantral and

early antral follicles

Menstrual Cycle

At the start of each menstrual cycle, 10-25 the

follicles begin to develop into larger follicles

In humans, usually one of the larger follicles in one ovary starts to grow rapidly on ± the 6thday, becomes the dominant follicle

The dominant follicle continues to develop, and

others (in both ovaries) regress and become a

degenerative process called

atresia

(an example of

programmed cell death, or

apoptosis

)

Ovulation

Mature follicle (Graafian follicle): ± 1,5 cm in

dia eter, that it alloo s out o ovary’s surfa e

Ovulation occurs when the thin walls of follicle

and ovary at site where they are joined rupture

because of enzymatic digestion

Secondary oocyte surrounded by its tightly

adhering zona pellucida and granulosa cells, as

well as cumulus, is carried out of ovary and onto

ovarian surface by antral fluid

Ovulatio …..

Occasionally, 2 or more follicles reach

maturity and more than 1 egg may be

ovulated

This is the most common of cause of

multiple births

In such cases, siblings are fraternal, not

identical, because the eggs carry different

sets of genes

LH

Follicular steroid hormones (progesterone) Proteolytic enzymes

(collagenase)

Follicular hyperemia and

Prostaglandin secretion

Weakened follicle wall Plasma transudation into follicle

Degeneration

of stigma Follicle swelling

Follicle rupture

Evagination of ovum

Indicators of Ovulation

A surge in LH secretion triggers ovulation

- Ovulation normally occurs ± 9 h after the peak of LH surge - The ovum lives for ± 72 h after ovulation, but it is

fertilizable for a much shorter time

Research shows:

> Intercourse on the day of ovulation: pregnancy 36% > Intercourse on days after ovulation: pregnancy 0

> Intercourse 1-2 d before ovulation: pregnancy 36%

> A few pregnancies resulted from intercourse 3-5 d before ovulation (8% on day 5 before ovulation)

- Thus, some sperms can survive in the female genital tract and fertilize the ovum for up to 120 h before ovulation, but the most fertile period is clearly 48 h before ovulation

I di ators of Ovulatio …..

A change (usually rise) in

basal body temperature

caused by secretion of progesterone, since

progesterone is thermogenic

- The rise starts 1-2 d after ovulation

- Obtaining an accurate temperature chart should

use a digital thermometer and take oral/rectal

temperatures in the morning before getting out

of bed

- Temperature change at the time of ovulation is

probably caused by the increase in progesterone

secretion

Basal body temperature and plasma LH and FSH concentrations (mean ± SE) during the normal human menstrual cycle

Formation of Corpus Luteum

After mature follicle discharges its antral fluid and egg, it collapses around antrum and undergoes rapid transformation

Granulosa cells enlarge greatly, and entire glandlike structure formed, known as corpus luteum (CL)

CL secretes estrogen, progesterone, inhibin

If the discharged egg (now in a fallopian tube) is not fertilized, CL reaches its maximum development

within ± 10 days.

CL then rapidly degenerates by apoptosis

It leads to menstruation and beginning of a new menstrual cycle

Granulosa Cell

Primordial follicles surrounded by a single layer of

granulosa cells

Granulosa cells secrete: - estrogen ,

- small amounts of progesterone just before ovulation

- peptide hormone inhibin

During childhood granulosa cells secrete: - nourishment for ova

Gra ulosa Cell…..

Further development from primordial follicle stage is characterized by

- an increase in size of oocyte

- a proliferation of granulosa cells into multiple layers - separation of oocyte from inner granulosa cells by a

thick of material: zona pellucida

Granulosa cells produce one or more factors that act on primary oocytes to maintain them in meiotic arrest

Gra ulosa Cell…..

Inner layer of granulosa cells remains closely

associated with oocyte by means of

cytoplasmic processes

that

traverse zona

pellucida

and form

gap junctions

with oocyte

Nutrients and chemical messengers

are passed

to oocyte through gap junctions

Granulosa cells produce one or more factors

that act on primary oocytes

to maintain them

in meiotic arrest

Theca Formation

As follicle grows by mitosis of granulosa cells,

connective tissue cells surrounding granulosa

cells differentiate and form layers known as

theca

Shortly

after theca formation

,

-

Primary oocyte

reaches

full size

(115



m in

diameter)

-

Antrum

(fluid-filled space) begins to for in

the midst of granulosa cells as result of fluid

they secrete

Illustration of an ovary shows sequential development of follicle, the formation of corpus luteum and follicular atresia

Process of Atresia

Atresia is not limited to just antral follicles, follicles

can undergo atresia

at any stage

This process is already occurring

in utero

so that

the 2-4 million follicles and eggs are present at

birth represent only a small fraction of those

present at earlier time in the fetus

Atresia then

continues all through pubertal life

so

that only 200,000-400,000 follicles remain when

active reproductive life begins.

Pro ess of Atresia…..

Therefore, 99,99 % of ovarian

follicles present at birth will

undergo atresia

Sites of Synthesis of Ovarian Hormone

Estrogen is synthesized and released into blood:

- during follicular phase mainly by granulosa cells

- after ovulation, by CL

Progesterone is synthesized and released into

blood:

- in very small amounts by granulosa and theca

cells just before ovulation

- major source is CL (after ovulation)

Inhibin is synthesized and released into blood:

- by granulosa cells

Interactions between theca and granulosa cells in estradiol synthesis and secretion

Ovarian Cycle

1. The follicular phase:

- ovarian follicle growth

- ovulation

2. The luteal phase:

Uterine Cycle

1. Proliferative phase:

-

estrogen



estrogen phase

-

before ovulation

2. Secretory phase:

-

progesterone



progestational phase

-

after ovulation

3. Menstruation

Relative concentrations of anterior pituitary gland hormones (FSH – LH) and ovarian Hormones (estrogen – progesterone) during a normal female sexual cycle. Note the relationship of the hormones to the ovarian and uterine cycles

Cyclical Changes in Cervix

The mucosa of cervix does not undergo cyclical

desquamation

There are regular changes in cervical mucus:

- Estrogen makes the mucus thinner, watery, and more

alkali e → pro otes the survival a d tra sport of sper s - At the time of ovulation the mucus is:

> thinnest and fern-like pattern on slide

> its elasti ity i reases → a drop a e stret hed i to a long (8 - ≥ , a d thi thread

- Progesterone makes the mucus thick, tenacious, and cellular

- After ovulation and during pregnancy: thick, no pattern

Microscopic of patterns formed of cervical mucus on dried smeared slide. Progesterone makes the mucus thick and cellular.

In anovulatory, no progesterone is present to inhibit fern-like pattern

Estrogen:

fern-like pattern

Estrogen,

no progesterone: Fern-like pattern Progesterone:

Cyclical Changes in Vagina

Under influence of estrogen:

- the vaginal epithelium becomes cornified that

can be identified in the vaginal smear

Under influence of progesterone:

- secretion of thick mucus

- the vaginal epithelium proliferates and

becomes infiltrated with leukocytes

The cyclical changes in vaginal smear in rats are

relatively marked; in humans and other species

are similar, but not so clear cut

Cyclical Changes in Breast

Although lactation normally does not occur until the end of pregnancy, cyclical changes take place in the breasts during the menstrual cycle

Estrogens cause proliferation of mammary ducts Progesterone causes: growth of lobules and alveoli

The breast swelling, tenderness, and pain experienced by many women during the 10 day preceding

e struatio ← due to diste tio of the du ts,

hyperemia, and edema of the breast interstitial tissue All the changes regress along with symptoms, during menstruation

Normal Menstruation

Menstrual blood is predominantly arterial, only 25% of the blood being of venous origin

Containing tissue debris, prostaglandins, and relatively large amount of fibrinolysin from endometrial tissue

Fi ri olysi lyses lots → o lots i e strual lood

Usual duration is 3-5 d, but 1-8 d can occur normally The average amount of blood lost is 30 ml (range

normally from light spotting – 80 ml)

The amount of blood affected by various factors,

including the thickness of endometrium, medication, and diseases that affect clotting mechanism

Anovulatory Cycles

Anovulatory cycles are common for the first 12-18 months after menarche and before the onset of menopause

Whe ovulatio does ot o ur → o CL → effe ts of

progesterone on endometrium are absent

Estrogens continue to cause growth, and proliferative endometrium becomes thick enough to break down and begins to slough

The time it takes for bleeding usually < 28 d from the last menstrual period

BIOSINTESIS DAN

MEKANISME KERJA

HORMON REPRODUKSI WANITA

Kuliah 3

Rahmatina B. Herman

Bagian Fisiologi

Ovarian Sex Hormones

Types of ovarian sex hormones:

1. Estrogens

The most important of estrogens is estradiol

2. Progestins

The most important of progestins is progesterone Production:

> Non-pregnant: by - ovaries

- adrenal cortices

> Pregnancy: by - ovaries

- placenta

Ovarian

Se Hor o es…..

Transport to target organ:

> Loosely bound with plasma albumin

> More tightly bound with a beta globulin: sex binding globulin

- specific estrogen-binding globulin

- specific progesterone-binding globulin

Mechanism of action:

> Location of receptors: - Cell interior

> Signal transduction mechanism:

- Receptors directly alter gene transcription

> Only free hormone can diffuse across capillary walls and encounter its target cells

Types of Estrogens

Beta-estradiol (17β-estradiol):

- major estrogen

- synthesized by ovaries

- strength: 12x estrone and 80x estriol

• Estrone

- by adrenal cortices, ovaries, and some other tissues

• Estriol

- oxidative product from estradiol and estrone - by liver

Synthesis

Cholesterol

Androstenedione

Testosterone

Estrone

Estradiol

Secreted by Ovaries

Aromatase

Sy thesis…..

The naturally estrogens (17β-estradiol, estrone, and estradiol) are C18 steroids

The biosynthesis of estrogens depends on the enzyme aromatase (CYP19), which converts testosterone to estradiol and androstenedione to estrone

The reaction of converting androstenedione to estrone also occurs in:

- fat - liver - muscle - brain

Synthesis by Ovaries

Estrogen is synthesized and released into blood

- during follicular phase mainly by granulosa cells

- after ovulation by corpus luteum

- during pregnancy by placenta

Granulosa cells require help to produce estrogen

because they are deficient in the enzymes required to produce androgens that are the precursors of estrogen They are aided by theca cells

Requires interplay of both types of follicle cells and both pituitary gonadotropins (FSH and LH)

Synthesis by

Ovaries…..

Ovarian follicle

(Diffusion₎ Theca cells

Synthesize androgens

Granulosa cells

Convert androgens to estrogen

Sy thesis y Ovaries…..

Theca interna cells have many LH receptors

LH acts via cAMP to increase conversion of cholesterol to androstenedione

Theca interna cells supply androstenedione to granulosa cells

Estradiol produced by granulosa cells when provided with androgen and secreted into follicular fluid

Granulosa cells have many FSH receptors

FSH facilitates the secretion of estradiol by acting via cAMP to increase aromatase activity

Secretion

Concentration of estradiol in plasma during menstrual cycle is depend on menstrual phase

Almost of this estrogen comes from ovary

Two peaks of secretion occur: one just before ovulation and one during the midluteal phase Estradiol secretion rate is:

- 36 μg/d in the early follicular phase - 380 μg/d just before ovulation

- 250 μg/d during midluteal phase

After menopause estrogen secretion declines to low levels

Development of Brain

At least in some species, the development of the brain as well as the external genitalia is affected by

androgens early in life.

In rats, a brief exposure to androgens during the first few days of life causes the male pattern of sexual

behavior and the male pattern of hypothalamic

control of gonadotropin secretion to develop after

puberty. In the absence of androgens, female pattern develop

In monkeys, similar effects on sexual behavior are produce by exposure to androgens in utero, but the patter of gonadotropin secretion remains cyclical

Develop e t of Brai …..

In humans, early exposure of female fetuses to

androgens also appears to cause subtle but significant masculinizing effects on behavior

However, women with adrenogenital syndrome due to congenital adrenocortical enzyme deficiency develop normal menstrual cycles when treated with cortisol. Thus, the human, like the monkey, appears to retain

the cyclical pattern of gonadotropin secretion despite exposure to androgens in utero

Tugas

Perkembangan anatomi sistem

reproduksi wanita sampai lahir