Gonadal Function

Reporters:
Alvin Roxas
Jovel Angeline Dizon
Claire Nicole Ocampo
Reigna Jeanne Tiongco
 The Testes
• By the 6th week of development in both
sexes, the primordial germ cells have
migrated from their extraembryonic
location to the gonadal ridges, where they
are surrounded by the sex cords to form a
pair of primitive gonads. Whether
chromosomally 46 XX or 46 XY, the
developing gonad at this stage of
development is bipotential.
 • Three important steps in sexual differentiation and
the development of the normal male phenotype.

1st 2nd 3rd

The differentiation of The development of the The development of the

bipotential gonad internal reproductive external genitalia that
primordia (identical in tract, initiated by fetal requires testosterone
both XX and XY fetuses) testicular androgen and, in some target
into the testes that production. In male tissues, its more potent
secrete testosterone, fetuses, this requires the metabolite 5α-
which is under the presence of AMH that dihydrotestosterone
control of the SRY causes involution of the (DHT).
protein coded by that Y müllerian ducts, the
chromosome gene. anlage for the female
type reproductive tract.
• Several genes are important for normal gonadal differentiation (and their
mutations may lead to disorders of sexual differentiation).
• Steroidogenic factor 1(SF-1)
-- is important for differentiation and maintenance of both gonadal and
adrenal tissue, increasing the synthesis of testosterone and reducing its
conversion to estradiol via the transcriptional regulation of the hydroxylases
and P450 aromatase, respectively. It may also regulate transcription of the
AMH2 gene in synergy with WT1.
Testicular descent is regulated by the protein product of gene Insl3, which is
a member of the insulin-like family and is secreted by Leydig cells. Insl3
seems to be important in gubernaculum formation, and mutations in its
gene have been shown to be linked with bilateral cryptorchidism in male
mice, and in addition, Insl3 protein may also be a biomarker for Leydig cell
function. Insl3 also seems to play a role in female fertility .
 Functional Anatomy of the Male Reproductive
•
Tracttesticular enlargement that results from rising
Adult testes are paired, ovoid organs that • The earliest sign of puberty in boys is
hang from the inguinal canal by the
spermatic cord, which comprises a luteinizing hormone (LH) and follicle-
neurovascular pedicle, vas deferens, and stimulating hormone (FSH). After puberty,
cremasteric muscle. throughout adulthood, and until late in old age,
• Two anatomical units: a network of testosterone helps with sperm production and
tubules, known as the seminiferous maintains secondary sexual characteristics.
tubules, and an interstitium.
• The tubules contain germ cells and • The sperm move sequentially through the
Sertoli cells and are responsible for tubuli recti; rete testes; ductuli efferentes
sperm production. testes; the head, body, and tail of the
• The testes serve dual functions, which epididymis; and, finally, into the vas deferens.
include (1) production of sperm and Various secretory products of the seminal
(2)production of reproductive steroid vesicles and prostate mix with sperm to form
hormones. In the embryonic stage, the the final product: semen. Seminal vesicle
dominant male sex hormone, testosterone secretions are rich in vitamin C and fructose,
(T), aids in development and important for the preservation of motility of the
differentiation of the primordial gonads. sperm.
 Physiology of the Testicles
Spermatogenesis
Sperm are formed from stem cells called spermatogonia. The spermatogonia undergo mitosis
and meiosis; finally, the haploid cells transform to form mature sperm. The mature sperm has
a head, body, and tail, which enables it to swim for the purpose of forming a zygote with the
haploid ovum. Certain spermatogonia stagger division so that sperm production is
uninterrupted and continuous. The Sertoli cells are polyfunctional cells that aid in the
development and maturation of sperm.

Hormonogenesis
Testosterone, the predominant hormone secreted by the testes, is controlled primarily by two
ituitary hormones: FSH and LH. Because these hormones were first described in women, they
are named in reference to the menstrual cycle. Both hormones are produced by a single group
of cells in the pituitary called gonadotrophs. FSH acts primarily on germinal stem cells and LH
acts primarily on the Leydig cells located in the testicular interstitium—that synthesize
testosterone. Gonadotropins (LH and FSH) are glycoproteins and share an alpha subunit with
thyroid-stimulating hormone (TSH) and hCG. The beta subunit confers biological specificity for
them.
Hormonal Control of Testicular Function

• GnRH is synthesized in neurons situated in the arcuate nucleus and other nuclei of the
hypothalamus and is released into the portal hypophyseal system that, in turn, determines the
production of LH and FSH from the pituitary gland.
• Impaired pulse generation of GnRH leads to inadequate production of LH and FSH, resulting
in hypogonadism.
• Testosterone is the principal androgen hormone in the blood, and after puberty, the testes
secrete 4 to 10 mg daily and less than 5% is derived from adrenal precursors such as
dehydroepiandrosterone (DHEA) and androstenedione. It is largely bound, with 2% to 3% free.
About 50% of testosterone is bound to albumin and about 45% is bound to sex hormone–
binding globulin (SHBG).
•Testosterone and inhibin are the two hormones secreted by the testes that provide feedback
control to the hypothalamus and pituitary.
• The actions of both testosterone and FSH on Sertoli cells are synergistic, permitting
completion of spermatogenesis. FSH stimulates production of an androgen receptor that makes
the Sertoli cell responsive to androgen and, in turn, androgens stimulate synthesis of FSH
receptors. Feedback on FSH is attributed to inhibin.
 Cellular Mechanism of Testosterone Action
• Testosterone enters the cell and converts to DHT in cells rich in 5α-reductase, such
as some hair follicles and prostate. DHT and testosterone complex with an
intracellular receptor protein and this complex bind to the nuclear receptor, effecting
protein synthesis and cell growth.

Physiologic Actions of Testosterone

• Prenatal Development
Early in development, embryos have primordial components of the genital tracts of both
sexes. The primitive gonads become distinguishable at about the 7th week of embryonic
stage. Both chorionic gonadotropins and fetal LH stimulate production of testosterone by the
fetal Leydig cells.
• Postnatal Development
Testicular function is reactivated during puberty after a period of quiescence to produce
testosterone that results in development of secondary sex hair (face, chest, axilla, and pubis),
enhanced linear skeletal growth, development of internal and external genitalia, increased
upper body musculature, and development of larynx and vocal cords with deepening of the
voice.

• Effect on Spermatogenesis
Stimulation of Leydig cells induces production of testosterone. Testosterone, acting with FSH,
has paracrine effects on the seminiferous and Sertoli cells, inducing spermatogenesis.
Exogenous overuse or abuse of testosterone, such as occurs with some athletes, will reduce
the high intratesticular concentration of testosterone, leading to reduction of sperm production.

• Effect on Secondary Sexual Effects

Failure to develop secondary sexual characteristics should prompt evaluation for
hypogonadism or constitutional delay in boys. Loss of secondary sexual characteristics might
occur gradually and should prompt evaluation for hypogonadism because, among other
effects, low testosterone levels lead to loss of bone mass and development of osteoporosis in
males at any age.
Disorders of Sexual Development and
Testicular Hypofunction
• Pubertal development could be premature (precocious) or
delayed, even if development is normal at birth
• Precocious sexual development results from premature
exposure of sex steroids, which might arise from early
gonadotropin secretion or production by the adrenal
glands or testes.
 Hypergonadotropic Hypogonadism
- Incorporates a group of disorders
- Characterized by low testosterone, elevated FSH or LH, and impaired sperm production.

Klinefelter’s syndrome
• Most common karyotype (47, XXY
• have small firm testicles (<2.5 cm)
• Gynecomastia is commonly present
• caused by the presence of an extra chromosome

Testicular feminization Syndrome

• The most severe form of androgen resistance syndrome,
• Kayotype: 46 XY
• resulting from mutations of the androgen receptor and impaired androgen actions in target tissues
 
5α-Reductase Deficiency
• Is a condition that affects male sexual development before birth and duting puberty
• a rare cause of androgen insensitivity and results in a mutation encoding the type 2 isoenzyme,
maps to chromosome 2p23, and is expressed in XY males.
Myotonic dystrophy
• Is inherited in an autosomal dominant fashion
• Presents with primary hypogonadism, frontal balding, diabetes, and muscle weakness, atrophy,
and dystonia (an inability of the muscle to relax adequately after contraction).
• Testicular failure typically presents in the fourth decade of life;
• Primary hypogonadism occurs with primarily germ cell compartment failure (i.e.,
oligozoospermia and infertility), with elevated serum FSH
• Failure of Leydig cell compartment resulting in low serum testosterone, elevated LH
concentrations, and testicular atrophy occurs.

TYPES: Other forms are:

Type 1 (DM1) also called Steinert’s disease • DM3
Type 2 (DM2 )also called as proximal myotonic • DM4
• DMX
 
Testicular Injury and Infection
• Postpubertal mumps infection can result in mumps orchitis and permanent testicular injury.
• Testicular damage due to viral orchitis and HIV infection has also been reported.
• Radiation and chemotherapy for cancer can also result in long-term damage
Sertoli Cell–Only Syndrome
• Characterized by a lack of germ cells 
• Men present with small testes, high FSH levels, azoospermia, and normal
testosterone levels.
• Testicular biopsy is the only procedure to confirm this diagnosis

Hypogonadotropic Hypogonadism
- Hallmark occurrence of low testosterone levels together with low or inappropriately
normal FSH or LH levels.

Kallmann’s Syndrome
• Is a result of an inherited, X-linked recessive trait that manifests as hypogonadism
during puberty.
• The frequency of this syndrome is 1 of 10,000 males.
• Certain men also have red-green color blindness, congenital deafness, or
cerebellar dysfunction.
Hyperprolactinemia
• Prolactin elevation resulting from any cause (drug induced or prolactin-producing
tumors of the pituitary)
• Function: stimulate the production of colostrum and breast milk in mammary
glands after childbirth
• Can result in hypogonadotropic hypogonadism due to impairment of pulsatile
secretion of FSH and LH,
Type 2 diabetes
• Is also associated with hypogonadotropic hypogonadism in at least 25% of men.
• Characterized by low free or total serum concentrations of testosterone and
inappropriately low LH.
• Mechanism underlying a combination of both insulin resistance (insulin action
seems to be important for LH release by gonadotropes) and inflammation
(hypogonadism in type 2 diabetic males was seen to be associated with high C-
reactive protein levels, an inflammatory marker).
Age
• There is a gradual reduction in testosterone after age 30, with an average decline of about
110 ng/dL every decade.
• The Baltimore Longitudinal Study of Aging revealed “hypogonadism” (reduced total
testosterone concentrations) of 19% at age 60, 28% at age 70, and 49% at age 80, with
free testosterone concentrations much lower in these men.
• Age is also associated with elevation of SHBG by about 1% per year. Similar findings
emerged from the Massachusetts Male Aging Study, which showed 1.6%/year decline in
total testosterone levels; and 2% to 3%/year decline in bioavailable testosterone (free and
albumin-bound testosterone) levels.
Pituitary disease
• Acquired hypogonadism can follow injury to the pituitary.
Opioid use
• Long-term or continuous use of narcotics has been linked to severe hypogonadotropic
hypogonadism and even decrease in male fertility.
Obstructive sleep apnea
• It is unclear if sleep apnea leads to hypogonadotropic hypogonadism or if the obesity
leads to decreased testosterone levels.
The Ovaries: Early Ovarian
Development
● If no Y chromosome or TDF is present, the gonad,
by default, forms an ovary; the cortex develops,
the medulla regresses, and oogonia begin to
develop within follicles.
● Beginning at about the end of the 3rd month, the
oogonia enter meiosis I, but this process is
arrested at a stage called dictyotene.
● It is evident that the gonads are paired bilateral
structures.
● The gonadotropins from the pituitary gradually
take over the role of maternal placental hCG, and
fetal pituitary LH and FSH.
 Pubertal Changes of Ovarian
Function
• The onset of puberty is
characterized by increasing
• The ovaries are paired organs that
perform the dual functions of
secretion of LH and FSH that gamete (ovum) and steroid
stimulates gonadal activity and is hormone production.
driven by increased activity of the • The primordial reproductive cells in
hypothalamic GnRH neurons. the female typically produce a
• Both LH and FSH are involved in solitary gamete.
the control of steroidogenesis. • Ovarian and menstrual events are
• The genes coding LH and FSH carefully synchronized: among the
receptors are on chromosome hypothalamus, pituitary, and
2p21. ovaries.
• Before the onset of puberty, both • In the absence of
LH and FSH are secreted in small implantation, the uterine lining is
amounts. shed, resulting in menses.
Functional Anatomy of the Ovaries
• The ovaries are oval organs that lie in the
pelvic fossa, formed by the posterior
and lateral pelvic wall, and attach to the
posterior surface of the broad ligament by
the peritoneal fold.
• Are positioned near the fimbrial end of the
fallopian tubes.
• An adult ovary averages 2 to 5 cm in
length, weighs an average of 14 g,
and typically contains 2 to 4 million primordial
follicles.
• Typically, all but one of these follicles
will then atrophy, in a process termed the
follicular phase.
• The single remaining follicle—known as the graafian follicle
—is composed of an outer and inner layer encasing a central
fluid-filled cavity and a layer of cells known as the granulosa
layer.
• The maturing ovum attaches to the inside of the follicle via
cells
derived from granulosa cells, called cumulus cells.
• During the luteal phase of the ovarian cycle, the graafian
follicle releases its ovum in response to ovarian stimulation by
LH.
• When the ovum is extruded, the graafian follicle undergoes a
morphologic change with hypertrophy of the theca and granulosa
cells to become the corpus luteum. This process is called
luteinization.
 Hormonal Production by the Ovaries
ESTROGEN
• Naturally synthesized estrogens
are carbon-18 compounds.
• The principal estrogen produced in
the ovary is estradiol.
• Estrone and estriol are primarily
metabolites of intraovarian and
extraglandular conversion.
• It promotes breast, uterine, and
vaginal development and also affect
the skin, vascular smooth muscles,
bone cells, and the central nervous
system.
PROGESTERONE
• Is a carbon-21 compound within the
steroid family and is produced
by the corpus luteum.
• Induces the secretory activity of
those endometrial glands that have
been primed by estrogen.
• Other effects: thickening of the
cervical mucus, reduction of uterine
contractions, and thermogenic effect.
• Is the dominant hormone
responsible for the luteal phase, and
deficiency results in failure of
implantation of the embryo.
 Hormonal Production by the Ovaries
ANDROGEN
• Ovaries produce the androgens
androstenedione,
dehydroandrostenedione,
testosterone, and DHT, all of which
are carbon-19 compounds.
• Excess production of ovarian
androgens in women leads to
excess hair growth (hirsutism),
loss of female characteristics, and
—in severe cases—development
of overt male secondary sexual
features.
OTHERS
• Inhibins A and B are hormones that
inhibit FSH production.
• Activin is a hormone that enhances
FSH secretion and induces
steroidogenesis.
• Folliculostatin, relaxin, follicle
regulatory protein, oocyte maturation
factor, and meiosis-inducing
substance are hormones that appear
to have important, yet not clearly
characterized, functions.
 The Menstrual Cycle
-The menstrual cycle is considered to start on the first day of menses.

Two phases of Menstrual Cycle:

THE FOLLICULAR PHASE

• Begins with the onset of menses and ends on the day of LH surge.
• The ovary secretes very little estrogen or progesterone.
• Rise in FSH stimulates estrogen production.

THE LUTEAL PHASE

• The start of the luteal phase is marked by the extrusion of the ovum approximately 36
hours after this LH surge, with subsequent luteinization of the Graafian follicle to form the
corpus luteum.
• The corpus luteum secretes progesterone to aid in the implantation of the embryo.
• The typical duration of menstrual bleeding is 3 to 5 days, with blood loss averaging 50 mL.
 Hormonal Control of Ovulation
• The central control of FSH and LH secretion resides in the GnRH pulse generator.
• Positive and negative feedback responses exist among estrogen, progesterone, LH, and FSH
production.
• During reproductive years, FSH levels are elevated early in the follicular phase.
• A mid-cycle surge in LH production stimulates a series of events that culminate in ovulation, with FSH
levels falling after this event.

Precocious Sexual
Pubertal Development
-Occurs in response to premature exposure of
Development in tissues to sex steroids from any source.

the Female  Premature breast development

 Premature adrenarche
• Thelarche
• Pubic hair • Gonadotropins and gonadal steroid secretion help
• Menarche differentiate between them.
• DHEA or dehydroepiandrosteronesulfate (DHEAS)
 The TannerStaging System
Stages of breast development:
• Pre-pubertal
• Elevation of breast bud and papilla, areolar enlargement
• Elevation of breast tissue and papilla
• Elevation of areola and papilla in secondary mound above the level of the breast.
• Mature stage: recession of areola into the breast with projection of papilla only.
Stages of pubic hair development:
• Lanugo-type hair (pre-pubertal)
• Dark terminal hair on labia majora
• Terminal hair covering labia majora and spreading to the mons pubis.
• Terminal hair fully covering the labia majora and mons pubis.
• Terminal hair covering the labia majora, mons pubis, and inner thighs.
 Menstrual Cycle Abnormalities
Amenorrhea– absence of menses
• Primary amenorrhea - never menstruated by age 16.
• Secondary amenorrhea - had at least one menstrual cycle followed by absence of menses for a minimum
of 3 to 6 months.
• Oligomenorrhea - infrequent irregular menstrual bleeding, with cycle lengths more than 35 to 40 days.
• Menorrhagia - uterine bleeding for more than 7 days.

Hypogonadotropic Hypogonadism - deficiency resulting in decreased sex steroid production, is a common

cause of secondary amenorrhea.
Hypergonadotropic Hypogonadism - characterized by ovarian failure resulting in elevation of FSH
concentrations, with or without LH elevations.

Polycystic Ovary Syndrome- This common disorder can present in many ways:
 Infertility  Hyperlipidemia Or Dyslipidemia
 Hirsutism  Hypertension
 Chronic Anovulation  Ovarian ultrasound reveals multiple cysts in many patients.
Glucose Intolerance  Most patients with this disorder are overweight.

Hirsutism - is abnormal, abundant, androgen-sensitive terminal hair growth in areas in which terminal hair
follicles are sparsely distributed or not normally found in women.
Thank you!