CLINICAL CHEMISTRY
Herce
LECTURE / 2nd SEMESTER
CHAPTER 22:
THE TESTES
• Primordial germ cells migrate to the gonadal ridges, forming
primitive gonads.
• The gonad is bipotential, either 46 XX or 46 XY.
• In the presence of the Y chromosome, medullary tissue forms testes
with seminiferous tubules and Leydig cells, capable of androgen
secretion.
• Spermatogonia: derived from primordial germ cells, forms the walls
of the seminiferous tubules.
• Leydig cells: produce androgen, stimulating mesonephric ducts to
form male genital ducts.
• Three steps in sexual differentiation and development of the
normal male phenotype:
1. differentiation of bipotential gonad primordia into testes that
secrete testosterone
2. development of the internal reproductive tract
3. development of external genitalia that require testosterone
and its more potent metabolite 5α-dihydrotestosterone (DHT)
• Three genes involved in gonadal differentiation:
1. WT11
2. LIM12
3. FTZ-F1
Functional Anatomy of the Male Reproductive Tract
Adult testes - paired, ovoid organs that hang from the
inguinal canal by the spermatic cord, which comprises
 neurovascular pedicle
 vas deferens
 cremasteric muscle
Location: outside the body, encased by a muscular sac
• Blood flow regulates the temperature of the testicles to 2°C below
core body temperature, crucial for uninterrupted sperm production.
Two anatomical units:
1. network of tubules - seminiferous tubules
2. interstitium - tubules contain germ cells and Sertoli cells and
are responsible for sperm production
Functions of Testes:
1. production of sperm
2. production of reproductive steroid hormones
• Puberty marks the transition from a non-reproductive
state into a reproductive state and is associated with
adrenarche with increase in adrenal androgen and gonadarche.
Earliest sign of puberty: testicular enlargement that results from ↑
luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
Seminal vesicle secretions: rich in vitamin C and fructose (important
for the preservation of motility of the sperm)
Physiology of the Testicles
Spermatogenesis
• undergoes mitosis and meiosis
• Haplotype cells: transform into mature sperm
• Mature sperm: has a head, body, and tail for zygote formation.
• Certain spermatogonia stagger division for uninterrupted sperm
production.
• Sertoli cells: aid in sperm development and maturation.
Hormonogenesis
• Testosterone, the main hormone secreted by the testes, is regulated
by FSH and LH.
• Named after the menstrual cycle, these hormones are produced by
gonadotrophs.
• FSH: affects germinal stem cells.
TRANSCRIBED BY: JOLAN HERCE
Jolan F.
BSMT-3B
• LH: affects Leydig cells in the testicular insterstitium
• Gonadotropins: glycoproteins with an alpha subunit and a beta
Gonadal Function
subunit
Hormonal Control of Testicular Function
• Gonadotropin-Releasing Hormone (GnRH): produced in the
hypothalamus and released into the portal hypophyseal system
 Impaired GnRH generation leads to hypogonadism.
• Cholesterol conversion to pregnenolone is the first step in testicular
steroidogenesis.
• Testosterone and inhibin provide feedback control to the
hypothalamus and pituitary.
• 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.
• Leydig cell steroidogenesis of testosterone: primarily controlled by
LH secretion
• FSH acts on Sertoli cells to stimulate protein synthesis, inhibin, and
androgen-binding protein.
Serum levels of testosterone:
 ↑ 6 am
 ↓ 12 am
Cellular Mechanism of Testosterone Action
• Testosterone enters cells, converts to DHT in 5α-reductase-rich
cells.
• Complex binds to nuclear receptor, affecting protein synthesis and
cell growth.
Physiologic Actions of Testosterone
Prenatal Development
• Primitive gonads become distinguishable at the 7 th week of embryonic
stage.
• Chorionic gonadotropins and fetal LH stimulate testosterone
production by fetal Leydig cells.
• Hypothalamohypophyseal vascular connections in fetus release LH
between 11 and 12 weeks after conception.
• hCG, with LH-like action: accounts for testosterone production gap
• Testosterone exposure to the Wolffian duct differentiates male
genital tract components.
• Sertoli cells produce AMH for female primordial genital tract
regression.
• Scrotal skin's 5α-reductase converts testosterone to DHT.
• Drugs blocking this enzyme and DHT formation lead to male fetus
genitalia feminization.
CLINICAL CHEMISTRY Jolan F. Herce
BSMT-3B
LECTURE / 2nd SEMESTER
Postnatal Development • an autosomal dominant condition
• characterized by: primary hypogonadism, frontal balding,
diabetes, muscle weakness, atrophy, and dystonia, often presenting
in the fourth decade of life

Testicular Injury and Infection

• Post-pubertal mumps infection can cause mumps orchitis,
permanent testicular injury, viral orchitis, HIV infection, and long-
term damage from radiation and chemotherapy for cancer.

Sertoli cell-only syndrome

• condition where men lack germ cells, presenting with small testes,
high FSH levels, azoospermia, and normal testosterone levels,
confirmed by a testicular biopsy

Effect on Spermatogenesis
• Leydig cell stimulation triggers testosterone production, which, when
combined with FSH, stimulates seminiferous and Sertoli cells,
promoting spermatogenesis.
Effect on Secondary Sexual Effects
• Testosterone promotes growth and maintains secondary sexual
characteristics in adulthood, leading to prostate enlargement and
hairline recession.
• Low testosterone levels can cause bone mass loss and osteoporosis.
HYPOGONADOTROPIC HYPOGONADISM
 occurrence of low testosterone levels together with low or
inappropriately normal FSH or LH levels
Kallmann’s Syndrome
• X-linked form of congenital GnRH deficiency
• impairs GnRH secretion due to impaired migration of neurons
• Mutations in the KAL1 gene, found on the X chromosome, cause
idiopathic hypogonadotropic hypogonadism and Hallmann's
syndrome

Disorders of Sexual Development and Testicular Hypofunction

HYPERGONADOTROPIC HYPOGONADISM
 incorporates a group of disorders characterized by low
testosterone, elevated FSH or LH, and impaired sperm
production

Klinefelter’s Syndrome
• about 1 of 400 men due to an extra chromosome; common
karyotype is 47,XY.
• Men with this disorder have small (<2.5cm), firm testicles.
• Gynecomastia (enlargement of the male breast) can also be
present
• ↓ testosterone, ↑ FSH and LH
• These men also have azoospermia and resultant sterility.
• Men with mosaicism may produce some sperm and pregnancies
have been reported

Testicular Feminization Syndrome

• Severe form of androgen resistance syndrome causing lack of
testosterone action in target tissue.
• Physical development pursues female phenotype with fully
developed breast and female fat and hair distribution.
• Most men present for primary amenorrhea evaluation, revealing
lack of female internal genitalia.
• Biochemical evaluation shows N testosterone levels,
↑ FSH and LH levels, no response to exogenous testosterone.

5α-reductase deficiency
• causes androgen insensitivity in XY males, affecting DHT
concentrations
• causing physical development similar to females until puberty,
affecting male internal genitalia

Myotonic dystrophy

TRANSCRIBED BY: JOLAN HERCE

CLINICAL CHEMISTRY
LECTURE / 2nd SEMESTER
Hyperprolactinemia
Prolactin elevation from drug-induced or prolactin-producing
pituitary tumors can lead to hypogonadotropic hypogonadism due to
impaired pulsatile secretion of FSH and LH, possibly disrupting
GnRH pulsatile secretion.
Type 2 Diabetes
Hypogonadotropic hypogonadism, a condition characterized by low
testosterone concentrations and inappropriate low LH, is linked to
insulin resistance and inflammation in at least 25% of males with
type 2 diabetes.
Age
Testosterone levels gradually decrease after age 30, with an
average decline of 110 ng/dL every decade. Age is associated with
increased SHBG and bioavailable testosterone levels. Testosterone
deficiency, combined with hypogonadism and low serum
testosterone concentrations, prompts testosterone replacement
consideration.
Pituitary Disease
• Acquired hypogonadism due to tumors, surgical trauma, vascular
injury, autoimmune hypophysitis, or granulomatous/metastatic
disease.
• Rare cause: Hemochromatosis
Diagnosis of Hypogonadism
Testosterone Replacement Therapy
Testosterone should be administered only to a man who is
Hypogonadal.
The currently available modes of testosterone administration in the
United States are as follows:
1. Parenteral testosterone
• Cypionate and enanthate esters of testosterone available for
intramuscular injection.
• Peak testosterone level achieved in 72 hours, lasting 1 to 2 weeks.
• Weekly administration for lower peak and less fluctuation.
• Dosing range: 50 to 100 mg weekly or 200 to 250 mg once every 2
weeks.
TRANSCRIBED BY: JOLAN HERCE
Jolan F. Herce
BSMT-3B
• Dosage based on lean body mass, not weight.
• Aim: Maintain mid-dose level at normal ranges.
2. Transdermal testosterone patch therapy
• Provides physiologic testosterone levels.
• Enhances skin permeability for absorption.
• May cause local skin irritation.
3. Testosterone gel
• Daily application to non-genital skin.
• Gradual absorption.
• Provides normal testosterone levels for 24 hours.
• Concerns: potential transmission to female partners or children
4. Testosterone buccal pellet
• Placed twice daily.
• Local discomfort.
• Twice-daily dosing limits usage.
5. Testosterone pellet
• Recommends three to six 75 mg testosterone pellets every 3 to 6
months.
• Implanted into subdermal fat of buttocks, lower abdominal wall, or
thigh.
• Risks: pellet extrusion, infection, and fibrosis.
• Limited data on serum testosterone concentrations limits routine use.
Monitoring Testosterone Replacement Therapy
Regularly check prostate-specific antigen (PSA), blood counts, and
lipid levels after testosterone replacement, and consider clinical
evaluation for leg edema, sleep apnea, and prostate enlargement.
THE OVARIES
Early Ovarian Development
• The gonad forms an ovary without a Y chromosome or TDF.
• The cortex develops, the medulla regresses, and oogonia develop
within follicles.
• Oogonia: from primitive germ cells by a series of about 30 mitoses
o enter meiosis I at the end of the third month
o arrested at dictyotene stage
• Only about 400 mature into ova during the 30 years of female sexual
maturity.
• Estrogen formation in the fetal ovary begins early development.
• Gonadotropins from the pituitary gradually take over the role of
maternal placental hCG.
• Fetal pituitary LH and FSH peak near mid-gestation and fall to low
concentrations at birth.
• Postpartum, a smaller peak of LH and FSH occurs, stimulating
steroid secretion and neonatal milk production.
Pubertal Changes of Ovarian Function
• ↑ secretion of LH and FSH stimulates gonadal activity
• Ovaries perform gamete and steroid hormone production.
• Menstrual cycle, 28 days, prepares uterus for embryo implantation.
Functional Anatomy of the Ovaries
• Ovaries are oval organs located in the pelvic fossa, attached to the
broad ligament by the mesovarium.
• Adult ovaries are 2 to 5 cm long, weigh 14 g, and contain 2 to 4
million primordial follicles.
• Each ovarian cycle involves recruitment of a few primordial follicles
for maturation.
• Graafian follicle (single remaining follicle) is composed of an outer
and inner layer, a central cavity, and a granulosa layer
CLINICAL CHEMISTRY Jolan F. Herce
BSMT-3B
LECTURE / 2nd SEMESTER
o ovum attaches to the follicle via cumulus cells derived from Hormonal Control of Ovulation
granulosa cells • Controls FSH and LH secretion.
o releases its ovum in response to ovarian stimulation by LH • Rises estrogen levels post-menopause.
• Corpus luteum: rich in cholesterol, acts as a substrate for • Elevated FSH levels in follicular phase.
progesterone and estrogen production, maintaining the endometrium • Midcycle surges in LH production trigger ovulation.
for conception.
Pubertal Development in the Female
• Involves hormonal events.
• Leads to secondary sexual characteristics and adult weight.
Hormonal Production by the Ovaries • Thelarche, breast tissue development, pubic hair growth, menarche.
Estrogen
 carbon-18 compounds
 primarily produced in the ovary Precocious Sexual Development
 play a crucial role in breast, uterine, and vaginal development,
affecting various organs during reproductive periods
Menstrual Cycle Abnormalities
Progesterone
• 25 to 35 days
 carbon-21 compound • average 28-day duration.
 produced by the corpus luteum and induces endometrial gland Amenorrhea
secretion preparing the endometrium for embryo implantation o absence of menses
 thickens cervical mucus, reduces uterine contractions, and has a
thermogenic effect Type 1. Hypothalamic hypogonadism (low or normal
FSH and/or LH)
Androgens  Hypothalamic amenorrhea (anorexia nervosa, idiopathic,
 androstenedione, testosterone, and DHT exercise induced)
o can lead to hair growth, female characteristics loss, and  Kallmann’s syndrome
masculinization in severe cases  Isolated gonadotropin deficiency
Type 2. Estrogenic chronic anovulation (normal FSH
Others and LH)
 Inhibins A and B inhibit FSH production  Polycystic ovarian syndrome (LH > FSH in some patients 2:1
 Activin enhances FSH secretion and induces steroidogenesis. or greater)
 Folliculostatin, relaxin, follicle regulatory protein, oocyte  Hyperthecosis
maturation factor, and meiosis inducing substance have
unspecified functions. Type 3. Hyperthalamic hypogonadism (elevated FSH and/or LSH)
 Premature ovarian failure
The Menstrual Cycle  Turner’s syndrome
The Follicular Phase
• Beginning with menstruation.
• Ending with LH surge. Primary amenorrhea
• Ovarian secretes minimal estrogen/progesterone. o woman has never menstruated
• Enhances uterine epithelial cells and endometrial gland Secondary amenorrhea
development. o woman who has had at least one menstrual cycle
followed by absences of menses for a minimum of 3–6
The Luteal Phase months.
• Estrogen levels peak 1 day before ovulation, triggering LH surge. Oligomenorrhea
• LH phase begins with ovulation extrusion and luteinization of o irregular menstrual bleeding
Graafian follicle. o cycle lengths in excess of 35–40 days.
• Corpus luteum secretes progesterone for embryo implantation.
Menorrhagia
• Without fertilization, endometrial blood supply declines, leading to
o Uterine bleeding in excess of 7 days and is considered
shedding 14 days post-ovulation.
dysfunctional
• Menstrual bleeding lasts 3-5 days.

HYPOGONADOTROPIC HYPOGONADISM
• Deficiency in gonadotropin (FSH and LH) leading to decreased sex
steroid production.
• Common cause of secondary amenorrhea.
• Causes: weight loss, intense exercise, pituitary tumors, and
prolactinomas

HYPERGONADOTROPIC HYPOGONADISM
• Characterized by ovarian failure leading to FSH and LH elevations.

TRANSCRIBED BY: JOLAN HERCE

CLINICAL CHEMISTRY Jolan F. Herce
BSMT-3B
LECTURE / 2nd SEMESTER
• Ovarian failure occurs naturally between 45-55 years in American
women.
• Menopause, a natural event, results in elevated FSH and LH levels
with low estrogen levels.
• Premature ovarian failure is primary hypogonadism before 40,
resulting from congenital chromosomal abnormality or premature
menopause.
• Patients with Turner’s syndrome do not experience the same hot
flashes as those with secondary hypergonadotropic hypogonadism.
• Premature menopause can occur alone or in conjunction with other
endocrine gland failures.

Polycystic Ovary Syndrome

• Characterized by: infertility, hirsutism, hypertension
• Diagnosis: ovarian ultrasound
• Most patients are overweight, some normal.
• Symptoms reversed with weight loss and increased activity.
• Glucophage, diabetes treatment drug, normalizes menstrual cycles
and improves conception rates.

Hirsutism
CLASSIFICATION OF HIRSUTISM
• Functional (normal androgen levels with excess hair growth) or
true androgen excess (elevated androgens)
• Ovarian (LH mediated) or adrenal (adrenocorticotropin hormone
mediated)
• Peripheral conversion of androgens (obesity)
• Tumoral hyperandrogenism (ovarian, adrenal)
• Chorionic gonadotropin mediated

CAUSES OF HIRSUTISM
COMMON
 Idiopathic
 Polycystic ovary syndrome
UNCOMMON
 Drugs: danazol, oral contraceptives with androgenic
progestins
 Congenital adrenal hyperplasia
 Hyperprolactinemia
 Cushing syndrome
 Adrenal tumors
 Ovarian tumors

Estrogen Replacement Therapy

• Women's Health Initiative study enrolled 16,608 postmenopausal
women.
• Found increased incidence of invasive breast cancer and venous clot
formation.
• No benefit in cognitive decline or coronary artery disease.
• Reductions in bone loss, colon polyp formation, and menopausal
symptoms noted.
• Currently, estrogen replacement is a treatment option after risk
counseling.

TRANSCRIBED BY: JOLAN HERCE