Reproductive Physiology

● Gonads = endocrine glands

○ Functions = support the development and maturation of the male and female germ cells
○ Male gonads = testes
■ Responsible for development/maturation of sperm and the synthesis/secretion of
testosterone (male sex steroid hormone)
○ Female gonads = ovaries
■ Responsible for development/maturation of ova and the synthesis/secretion of estrogen
and progesterone (female sex steroid hormones)

Sexual Differentiation
Genetic Sex
● During the first 5 weeks of gestational life, gonads are indifferent or bipotential → are neither M or F
● At gestational week 7 in genetic males, the SRY gene (gene product of the sex-determining region of Y
chromosome) causes testes to start developing
● At gestational week 9 in genetic males, absence of SRY gene → ovaries start developing
● Normally determines gonadal sex
○ Gonads appear in males slightly before they appear in females

Gonadal sex
● Male gonads = testes
○ Have 3 cell types
■ Germ cells → spermatogonia
■ Sertoli cells → glycoprotein hormone = antimullerian hormone
■ Leydig cells → testosterone
○ Antimullerian hormone and testosterone = decisive in determining that the fetus is a phenotypic
male
■ If no testes → no antimullerian hormone or testosterone → fetus becomes a phenotypic female by
“default”
● Female gonads = ovaries
○ Have 3 cell types
■ Germ cells → oogonia
● Meiotic oogonia are surrounded by granulosa cells and stroma
○ In this configuration, they are called oocytes
● Remain in the prophase of meiosis until ovulation
■ Granulosa cells → estradiol
■ Theca cells → progesterone and estradiol
○ Ovaries do NOT synthesize antimullerian hormone or testosterone

Phenotypic Sex
● Males
○ Internal genital tract
■ Prostate, seminal vesicles, vas deferens, and epididymis
● Testosterone stimulates growth and differentiation of Wolffian ducts → epididymis, vas
deferens, seminal vesicles, and ejaculatory ducts
○ Testosterone from each testis acts ipsilaterally on its own Wolffian duct
○ Testosterone does not have to be converted to dihydrotestosterone
○ External genitalia
■ Scrotum, penis
● Differentiates at week 9-10
● Depends on the conversion of testosterone to dihydrotestosterone and the
presence of androgen receptors on target tissues
○ Testes secrete antimullerian hormone and testosterone → both are req to dev male phenotype
■ Antimullerian hormone causes atrophy of mullerian ducts
 ● Females
○ Internal genital tract
■ Fallopian tubes, uterus, and upper one-third of the vagina
● No antimullerian hormone → cannot suppress differentiation of mullerian ducts →
mullerian ducts differentiate into internal female tract
○ External genitalia
■ Clitoris, labia majora, labia minora, and lower two-thirds of the vagina
● Growth does not require any hormones, but growth to normal size depends on
presence of estrogen
○ Ovaries secrete estrogen, but not antimullerian hormone or testosterone
■ No testosterone → cannot stimulate growth and differentiation of Wolffian ducts into internal
male genital tract

Puberty

Gonadotropin Secretion over the Lifetime

● Secretion of gonadotropin-releasing hormone (GnRH) starts at week 4 of gestation
○ GnRH levels remain low until puberty
● Secretion of FSH and LH starts at week 10-12 of gestation
○ FSH and LH levels remain low until puberty
○ During childhood, FSH > LH levels
● At puberty, secretion of GnRH, FSH, and LH increases and becomes pulsatile
○ LH > FSH levels
○ In females, there is a 28 day cycle of gonadotropin secretion = menstrual cycle
● In senescence, gonadotropin secretion rates increase more
○ FSH > LH levels

Pulsatile Secretion of GnRH, FSH, and LH

● Primary event at puberty = initiation of pulsatile secretion of GnRH
○ This new pattern drives a parallel pulsatile secretion of FSH and LH by the anterior pituitary
■ This stimulates secretion of gonadal steroid hormones (testosterone, estradiol) → appearance of
secondary sex characteristics
○ Mechanism of pulsatile GnRH secretion is unknown
 ■ May be due to gradual maturation of hypothalamic neurons that synthesize and secrete
GnRH
■ Or may be due to CNS and nutritional status
● Extreme stress or caloric deprivation in girls → delays onset of puberty
○ Pulsatility of hypothalamic-pituitary axis = req for normal reproductive function
■ Cuz GnRH deficiency → delayed puberty
● One of the earliest events of puberty = appearance of large nocturnal pulses of LH during REM sleep
● Another early event = increased sensitivity of GnRH receptor in anterior pituitary
○ At puberty, GnRH upregulates its own receptor in anterior pituitary → secretes more FSH and LH at a
given concentration of GnRH
● Onset of maturational process at puberty = based on genetics and other factors
○ Menarche (onset of menses) = similar between mothers and daughters
○ Melatonin may be a natural inhibitor of GnRH release
■ Secreted by pineal gland
■ Levels are highest during childhood, decline in adulthood (→ inhibition of GnRH secretion)
■ Remove pineal gland → early puberty

Characteristics of Puberty
Boys
● Puberty is associated with activation of
hypothalamic-pituitary axis, Leydig cell
proliferation in testes, and increased
synthesis/secretion of testosterone by Leydig
cells
● Growth of testes due to increased #
seminiferous tubules
● Growth of sex accessory organs (prostate)
● Pronounced linear growth spurt; Epiphysis
closes when adult height is reached
● Facial, pubic, axillary hair increases as plasma
levels of testosterone increases
● Growth of penis
● Lowering of voice due to increased size of
larynx and vocal cords
● Spermarche (initiation of spermatogenesis)

Girls
● Puberty is associated with activation of
hypothalamic-pituitary axis, which drives the
synthesis of estradiol by ovaries
● First observable sign = budding of breasts
● Followed in 2 years by menarche
● Growth spurt and closure of epiphysis starts
and ends earliers than in boys
● Adrenarche = appearance of pubic and axillary hair
→ starts BEFORE menarche! Depends on increased
secretion of adrenal androgens
Male Reproductive Physiology
Structure of the Testes
● Testes lie in the scrotum, which is outside of the body cavity and is maintained at 35-36℃ (which is 1-
2℃ below body temperature)
○ This temp is maintained by a countercurrrent arrangement of testicular arteries and veins → facilitates
heat exchange
● Function = spermatogenesis and secretion
○ Lower body temperature = required for normal spermatogenesis
 ● 80% of testes in adult = seminiferous tubules
○ Produces sperm
○ Are convoluted loops that are arranged in lobules and surrounded by connective tissue
○ Epithelium lining the seminiferous tubules has 3 cell types:
■ Spermatogonia = stem cells
■ Spermatocytes = cells in the process of becoming sperm
■ Sertoli cells = support for developing sperm
● Functions (all to support spermatogenesis):
○ Provide nutrients to the differentiating sperm (which are isolated from the
bloodstream)
○ Form tight junctions with each other → creates a barrier between the testes and
bloodstream = blood-testes barrier
■ Selectively permeable → allows some substances (like testosterone) to
cross, but prohibits others (like noxious substances that might damage
the sperm)
○ Secrete aqueous fluid into lumen of seminiferous tubules → helps transport
sperm through tubules into the epididymis
○ Secrete androgen-binding protein into lumen of seminiferous tubule (near the
developing sperm cells) → helps to keep local lvl of testosterone high
● 20% of testes = connective tissue, interspersed with Leydig cells
○ Function of Leydig cells = synthesis and secretion of testosterone = male sex steroid hormone
■ Testosterone has local (paracrine) and endocrine effects
● Paracrine effects → supports spermatogenesis in testicular Sertoli cells
● Endocrine effects → target organs = skeletal muscle, prostate, etc
Spermatogenesis
Occurs continuously throughout the reproductive life of males (from puberty to senescence).
Occurs along the length of the seminiferous tubules
One full cycle = 64 days
Process:
1. Mitotic divisions of spermatogonia → generates
spermatocytes that are destined to become mature
sperm
2. Meiotic divisions of spermatocytes → decreases
chromosome number and produces haploid
spermatids
3. Spermiogenesis → spermatids are transformed into
mature sperm through the loss of cytoplasm and dev
of flagella

Temporal organization of spermatogenic cycle = spermatogenic wave → ensures that mature spermatozoa are prod
128 million sperm are produced daily
Storage of Sperm, Ejaculation, and Function of Sex
Accessory Glands
● Sperm leave the testes through ducts that carry
them to the epididymis
○ Epididymis = primary location for
maturation and storage of sperm
○ Sperm remain viable in the epididymis for several months
● Sexual arousal: contractions of smooth muscle around ducts → push the sperm through the epididymis
● Ejaculation: sperm are expelled into the vas deferens → urethra
● Ampulla of vas deferens
○ Another storage area for sperm
○ Secretes a fluid rich in citrate and fructose, which nourishes the ejaculated sperm
● Seminal vesicles
○ Secretes a fluid rich in fructose, citrate, prostaglandins, and fibrinogen
 ■ Prostaglandins assist in fertilization by reacting with cervical mucus (to make it more
penetrable by sperm) and inducing peristaltic contractions in uterus and fallopian tubes
(to propel the sperm up the female reproductive tract)
○ As the vas deferens empties is sperm into ejaculatory duct, each seminal vesicle contributes its
secretions (= nutrition for ejaculated sperm)
● Prostate gland
○ Adds its own secretions to the ejaculate
■ Is a milky aqueous solution rich in citrate, calcium, and enzymes
■ Is slightly alkaline → increases sperm motility and aids in fertilization by neutralizing acidic
secretions from the vas deferens and the vagina
● Semen
○ 10% = sperm
○ 90% = combined secretions of male sex accessory glands
● Ejaculated sperm can’t immediately fertilize an ovum - must reside in female reproductive tract for 4-6
hours in order for capacitation to occur
○ Capacitation: inhibitory factors in seminal fluid are washed free, cholesterol is withdrawn from
sperm membrane, surface proteins are redistributed, causes acrosomal reaction
■ Acrosomal reaction: acrosomal membrane fuses with outer sperm membrane → creates pores
through which hydrolytic and proteolytic enzymes can escape from the acrosome → creates path
for sperm to penetrate the protective coverings of the ovum
○ Ca influx into sperm → increases sperm motility → motion of sperm becomes whip-like
 Female Reproductive Physiology
● Ovaries + uterus + fallopian tubes = female reproductive tract
○ Female gonads = ovaries
■ Functions of ovaries: oogenesis and secretion of female sex steroid hormones (estrogen
and progesterone)
● Ovarian steroid hormones have paracrine and endocrine functions
○ Paracrine = support the development of ova
○ Endocrine = acts on target tissues (like uterus, breast, bone)
● Each ovary is attached to uterus by ligaments
○ Running through these ligaments = ovarian arteries, veins, lymphatic vessels, and nerves
● Ovary has 3 zones:
○ Cortex
■ Outer, largest zone
■ Lined by germinal epithelium
■ Contains all of the oocytes, each of which is enclosed in a follicle
● Ovarian follicles are responsible for steroid hormone synthesis
○ Medulla
■ Middle zone
■ Mixture of cell types
○ Hilum
■ Inner zone
■ Blood vessels and lymphatics pass through here
● Functional unit of ovaries = ovarian follicle
○ Follicle has one germ cell surrounded by endocrine cells
○ When fully developed, follicle functions to:
■ Provide nutrients for developing oocyte
■ Release oocyte at ovulation
■ Prepare vagina and fallopian tubes to aid in fertilization of the egg by a sperm
■ Prepare the lining of uterus for implantation of the fertilized egg
■ In the event of fertilization, maintain steroid hormone production for the fetus until the
placenta can assume this role

Oogenesis
● In the developing ovaries, primordial germ cells produce oogonia by mitotic divisions until weeks 20-24
○ Will have 7 million oogonia
● Starting in week 8-9, some of these oogonia enter prophase of meiosis and become primary oocytes
○ Meiotic process continues until 6 months after birth → all oogonia have become oocytes
○ Oocytes remain in suspended prophase
■ First meiotic division is not completed until ovulation!
○ There is also attrition of oocytes
■ At birth, only 2 million oocytes remain
■ At puberty, only have 400,000 oocytes
■ By menopause, few (if any) oocytes remain
■ Females do not produce new oogonia (unlike males)
● Development of ovarian follicles
○ First stage
■ Parallels prophase of oocyte
■ Lasts many years
● Shortest duration = 13 years (approximate age at first ovulation)
● Longest duration = 50 years (approximate age at menopause)
■ As primary oocyte grows, granulosa cells proliferate and nurture the oocytes with
nutrients and steroid hormones
■ Primordial follicle develops into primary follicle
■ Theca interna cells develop
■ Granulosa cells start secreting fluid
 ■ No follicle progresses beyond this stage in prepubertal ovaries
○ Second stage
■ Occurs more rapidly and takes place over 70-85 days
■ Only present in the reproductive period
■ In each menstrual cycle, a few follicles enter this sequence
■ Fluid with steroid hormones, mucopolysaccharids, proteins, and FSH accumulates in a
central area of the follicle = antrum
● Steroid hormones reach the antrum via direct secretion from granulosa cells
■ Granulosa and theca cells continue to grow
■ At the end of second stage, follicle becomes a graafian follicle
○ Third stage
■ Most rapid and occurs 5-7 days after menses
● Menses marks the end of the previous cycle
■ A single graafian follicle achieves dominants over its cohorts
● Rest of the cohorts will regress
■ Within 48 hours, the dominant follicle will grow to 20 mm
■ On day 14 (of a 28 day cycle), ovulation occurs
● Dominant follicle ruptures and releases its oocyte into the peritoneal cavity
● At this time, the first meiotic division is completed → secondary oocyte
○ Secondary oocyte enters the nearby fallopian tube → starts the second meiotic
division
○ In the fallopian tube, if have fertilization by sperm, then second meiotic division
is completed → produces haploid ovum with 23 chromosomes
● Residual elements of ruptured primary follicle form the corpus luteum
○ Composed of granulosa cells (primarily), theca cells, capillaries, and
fibroblasts
○ Synthesizes and secretes steroid hormones
■ Necessary for implantation and maintenance of zygote if
fertilization occurs
■ If fertilization occurs, corpus luteum will continue secreting steroid
hormones until placenta can do this (later in pregnancy)
○ If no fertilization, then corpus luteum regresses during the next 14 days
and is replaced by a scar = corpus albicans

Negative and Positive Feedback Regulation of Hypothalamic-Pituitary Axis

● Every 28 days, there’s a menstrual cycle = sequence of follicular development, ovulation, formation
and degeneration of corpus luteum
○ First 14 days = follicular phase = proliferative phase
■ Involves follicular development
 ■ Dominated by estrogen
■ FSH and LH stimulates synthesis and secretion of estradiol by follicular cells
● Estradiol has negative feedback on GnRH, FSH, and LH secretion
○ Midpoint of cycle = ovulation
■ Estradiol levels rise due to proliferation of follicular cells and stimulation of estradiol
synthesis (from follicular phase)
■ When have a high enough level of estradiol, estradiol has a positive feedback on GnRH
secretion and upregulates GnRH receptors → increases LH and FSH secretion
● This burst = ovulatory surge of FSH and LH → triggers ovulation of mature oocyte
○ Last 14 days = luteal phase = secretory phase
■ Dominated by the corpus luteum
■ Major hormone secretion = progesterone
● Causes negative feedback on GnRH, FSH, and LH secretion
● Granulosa cells produce inhibin → negative feedback on FSH
● Granulosa cells also produce activin → positive feedback on FSH

Actions of Estrogen and Progesterone

● In general, both are coordinated to support the reproductive activity of female, including:
○ Development of ovum
○ Development and maintenance of corpus luteum to sustain a fertilized ovum
○ Maintenance of pregnancy
○ Preparation of breasts for lactation
● Sometimes, estrogen and progesterone antagonize each other’s actions
○ In the menstrual cycle, estrogen secretion precedes progesterone secretion → prepares the target tissues to
respond to progesterone
■ EX: up-regulation of progesterone receptors by estrogen in several target tissues
● Without estrogen and its up-regulation of progesterone receptors, progesterone
has little bio activity
○ Progesterone down-regulates estrogen receptors in some target tissues, decreasing their
responsiveness to estrogen
● Development of the female reproductive tract
○ Uterus
■ Estrogen → cell proliferation, cell growth, increased contractility
■ Progesterone → increased secretory activity, decreased contractility
○ Fallopian tubes
 ■ Estrogen → stimulates ciliary activity and contractility → helps move sperm towards uterus
■ Progesterone → increases secretory activity, decreases contractility
○ Vagina
■ Estrogen → stimulates proliferation of epithelial cells
■ Progesterone → stimulates differentiation of epithelial cells, inhibits proliferation of epithelial
cells
● Menstrual cycle
○ Estrogen and progesterone → changes that occur in the endometrium, cervix, and vagina
■ Also cause feedback regulation of FSH and LH secretion
○ Follicular phase
■ 17-beta-estradiol secretion increases → prepares endometrial lining of uterus to accept a fertilized
ovum
■ Estradiol causes:
● Stimulates growth of the endometrium
● Stimulates growth of glands and stroma
● Stimulates elongation of the spiral arteries
○ Spiral arteries supply the endometrium
● Cervical mucus to become copious, watery, and elastic
○ On histo, cervical mucus = ferning
○ This watery mucus allows channels to form → creates openings in cervix through
which sperm can be propelled
○ Luteal phase
■ Progesterone causes:
● Endometrial proliferation slows and thickness decreases
● Uterine glands become more tortuous, accumulate glycogen in vacuoles, and
increase their mucus secretions
● Stroma of the endometrium becomes edematous
● Spiral arteries elongate more and become coiled
● Decreased quantity of cervical mucus → becomes thick and non-elastic
○ On histo, cervical mucus does not fern
○ Sperm cannot penetrate mucus (cuz no more opportunity for fertilization)
● Breasts
○ Depends on estrogen
○ Breasts = composed of lobular ducts lined by a milk-secreting epithelium
■ Small ducts converge and empty into larger ducts that converge at the nipple
■ All embedded in adipose tissue
○ Puberty: onset of estrogen secretion causes:
■ Lobular ducts grow
■ Areola enlarged (Areola = area around the nipple)
■ Increased amount of adipose tissue → gives breasts their characteristic female shape
○ Progesterone collaborates with estrogen by stimulating secretory activity in the mammary ducts
● Pregnancy
○ Highest levels of estrogen and progesterone = during pregnancy
■ Synthesized in early pregnancy by corpus luteum
■ Synthesized in mid-to-late pregnancy by placenta
○ Estrogen
■ Stimulates growth of myometrium
■ Stimulates growth of ductal system in breasts
■ Stimulates prolactin secretion
■ Stimulates enlargement of external genitalia
○ Progesterone
■ Maintains endometrial lining of uterus
■ Increases uterine threshold to contractile stimuli → preserves pregnancy until fetus is ready to be
delivered

Pregnancy
 ● If ovum is fertilized by sperm → fertilized ovum starts to divide → becomes the fetus
● Fertilization
○ Occurs within 24 hours of ovulation
○ Occurs in ampulla of fallopian tube
○ Once sperm penetrates ovum, second polar body is extruded → fertilized ovum starts to divide
● Blastocyst
○ Has 100 cells
○ Arrives in uterine cavity 4 days after ovulation
● Implantation
○ Blastocyst floats freely in uterine cavity for 1 day, then implants in endometrium of uterus 5 days
after ovulation
■ At this time, the blastocyst has an inner cell mass of cells (which will become fetus) and outer rim
of cells (= trophoblast, which invades endometrium and forms an attachment to the maternal
membranes → fetal portion of placenta)
○ Receptivity of endometrium to the fertilized ovum depends on low estrogen/progesterone ratio
■ Corresponds to the period of highest progesterone output by corpus luteum
○ Progesterone causes endometrium to differentiate into a specialized layer of decidual cells
■ Eventually, the decidua envelops the entire embryo
● Trophoblastic cells proliferate and form the syncytiotrophoblast
○ Function = allow blastocyst to penetrate deep into the endometrium
● Trophoblast secretes hCG 8 days after ovulation
○ hCG informs the corpus luteum that fertilization has occurred → tells it to continue synthesizing
progesterone and estrogen → maintains the endometrium for implantation
■ Therefore, hCG rescues corpus luteum from regression
○ Function of hCG beyond first trimester = unclear
● High levels of estrogen and progesterone → suppression of dev of the next cohort of ovarian follicles
● First few weeks of pregnancy
○ Production of hCG increases dramatically → will also excrete lots of hCG in urine
■ hCG in urine can be detected in pregnancy test 9 days after ovulation (even before the
next expected menses!)

Parturition
● These events occur near term and can contribute to parturition
○ Once the fetus reaches a critical size, distension of uterus will increase its contractility
■ Braxton Hicks contractions = uncoordinated contractions that start 1 month before birth
 ○ Near term, fetal hypothalamic-pituitary-adrenal axis is activated → fetal adrenal cortex produces
significant amounts of cortisol → cortisol increases estrogen/progesterone ratio → increased
sensitivity of uterus to contractile stimuli
■ Cuz estrogen increases contractility and prostaglandins decreases it
○ Increased estrogen/progesterone ratio → stimulates local production of prostaglandins (PGE2
and PGF2alpha)
■ Cuz estrogen increases prostaglandins and progesterone inhibits
■ Prostaglandins will:
● Increase intracellular Ca concentration of uterine smooth muscle → increases uterine
contractility
● Promote gap junction formation between uterine smooth muscle cells → permits
synchronous contraction of uterus
● Cause softening, thinning (effacement) and dilation of cervix early in labor
○ Oxytocin = powerful stimulant of uterine contractions
■ Uterine oxytocin receptors = up-regulated towards the end of gestation
■ Dilation of cervix stimulates oxytocin secretion → positive feedback
■ But maternal blood levels of oxytocin do not increase near term → unsure about the physio role
of oxytocin
● 3 stages of normal labor
○ First stage
■ Uterine contractions (originating at fundus and sweeping downward) will move the head off the
fetus towards the cervix → progressively widen and thins the cervix
○ Second stage
■ Fetus is forced through the cervix and delivered through the vagina
○ Third stage
■ Placenta separates from uterine decidual tissue and is delivered
■ Powerful contractions of uterus → constricts uterine blood vessels, limits postpartum bleeding
● After delivery of placenta, hormone concentrations return to pre-pregnancy levels
○ Except prolactin, cuz will have high levels of prolactin if mother is breastfeeding