Gonadal Hormones

.
 Hormonogenesis
 Testosterone: predominant hormone secreted
by the testes
 Controlled by pituitary hormones:
 Follicle-stimulating hormone (FSH)
acts primarily on germinal stem cells
 Luteinizing hormone (LH)
acts primarily on the Leydig cells
 l o c at e d in the testicular insterstitium
synthesize testosterone
Hormonal Control of Testicular
Function

GnRH: determines the production of LH and

FSH
 ↓ Pulse generation of GnRH = ↓ LH a n d FSH
=
hypogonadism
Testicular Steroidogenesis
Conversion of cholesterol to pregnenolone
 Cholesterol: trapp e d by endo c ytosis from
the
blood or synthesized within the Leydig cells
LH binds to the glycoprotein receptor in the
cell wall
Induces intracellular cyclic AMP production
Activates protein kinase A
Catalyzes protein phosphorylation
 Hormonal Control of
Testicular Function

 Testosterone: principal androgen hormone in the blood

 2%–3% free
 About 50% of testosterone is bound to albumin
 About 45% is bound to sex hormone–binding globulin (SHBG)
 Testosterone & inhibin: provide feedback control to the hypothalamus
and pituitary
 Hormonal Control of
Testicular Function

Testosterone concentration fluctuates in a

circadian fashion
Reflecting the parallel rhythms of LH a nd FSH
levels
Highest level is found at about 8 AM
Lowest level is found at about 8 PM
Cellular Mechanism of
Testosterone Action

Prenatal Development
 The primitive gonads b e c o m e distinguishable at about the seventh
week of embryonic stage.
 Both chorionic gonadotropins a n d fetal LH stimulate
production of testosterone by the fetal Leydig cells.
 Exposure of testosterone to the Wolffian duct leads to
differentiation of the various components of the male genital tract.
 Sertoli cells produce müllerian regression factor, which aids
in regression of the female primordial genital tract. The scrotal
skin is rich in 5-reductase, which converts testosterone to DHT.
 Fetal exposure to drugs that block this hormone leads to
feminization of the male fetus.
Cellular Mechanism of
Testosterone Action

Postnatal Development
 Development of secondary sex hair (face, chest, axilla, an d pubis),
enhanced linear skeletal growth, development of internal a n d
external genitalia, increased upper body musculature, a n d
development of larynx an d vocal cords with deepening of the
voice.
 Possible m o o d changes an d aggression are undesired effects that
may occur during puberty.
 The linear growth effects of testosterone are finite, with epiphysial
closure when genetically determined height is achieved.
 Hypogonadism during puberty leads to imprecise
closure of growth plates, leading to excessive height, long
limbs, a n d disproportionate upper an d lower body
segments.
Cellular Mechanism of
Testosterone Action

Testosterone enters the cell a n d converts to

dihydrotestosterone(DHT)by 5α-
reductase
DHT complexes with an
intracellular receptor protein
Complex binds to the nuclear receptor →
effecting protein synthesis a n d cell
growth
 Development
and Testicular Hypofunction
 Hypergonadotropic Hypogonadism
 low testosterone, elevated FSH or LH, and
impaired sperm production
 Klinefelter’s Syndrome
 Testicular Feminization Syndrome
 5-Reductase Deficiency
 Myotonic Dystrophy
 Testicular Injury and Infection
 Sertoli Cell–Only Syndrome
 Testicular Feminization
Syndrome
 Most severe form of andro g en resistance
syndrome
 Lack of testosterone action in the target tissue
 Physical d evelopment pursues the female
phenotype
 fully developed breast
 female distribution of fat a n d hair
 Men present with primary amenorrhea
 lack of female internal genitalia becomes apparent
 Testicular Feminization
Syndrome

Testicles are often undescended

 Failure to p rom ptly remove testic lesresults
in malignant transformation
Normal levels of testosterone
Elevated FSH an d LH levels
 No resp onse to a d ministration of
exogenous testosterone
 5-Reductase Deficiency
Genotype- XY
 Reduction in levels of the enzyme 5-
reductase → decreased testosterone levels
 Physic al d e velo pm ent is similar to the
female phenotype
Puberty: residual enzyme activity sufficiently
converts testosterone to
dihydrotestosterone, resulting in
development of a male phenotype
Klinefelter’s Syndrome

 Most c o m m o n karyotype is 47,XY

 Men with this disorder have small (2.5 cm),
firm testicles
 Gynecomastia
 Reduced production of testosterone
 FSH a n d LH levels are elevated
 Azoospermia → sterility
 Reduced bone density a n d breast cancer
 Klinefelter’s Syndrome

Me n with mosaicism

May some sperm
p regnancies ha ve and b een
produce
such men re p orted with
Elevated levels of FSH a n d LH
Induced increased aromatase activity
Elevated estrogen levels
 Myotonic Dystrophy

Inherited in an autosomal dominant

fashion
Hypogonadism
Muscle weakness
Frontal balding
Diabetes
Muscle dystonia
Testicular failure typically presents in
the fourth d e c a d e of life
 Testicular Injury and Infection

Postpubertal mumps infection

mumps orchitis
permanent testicular injury
Testicular d a m a g e
viral orchitis
HIV infection
Radiation a n d chemotherapy for
cancer
 Sertoli Cell–Only Syndrome

 Lack of germ cells

 Men present with:
small testes
high FSH levels
Azoospermia
normal testosterone levels
 Testicular biopsy is the only procedure to
confirm this diagnosis
 Development
and Testicular Hypofunction

Low testosterone levels together with low or

inappropriately normal FSH or LH levels
Hypogonadotropic Hypogonadism
Kallmann’s Syndrome
Hyperprolactinemia
Age
Pituitary Disease
 Kallmann’s Syndrome

 Inherite d , X-linked recessive trait that

manifests as hypogonadism during puberty
Anosmia (inability to smell)
Midline defects (cleft palate a nd lip)
 Certain men a lso re d -green
have blindness, c olor
congenital dysfunction
cerebellar d e a fness, or
 Hyperprolactinemia

Prolactin elevation
Drug-induced
Prolactin-producing tumors of the
pituitary
Age

 Gradual reduction in testosterone after age

30
 Average decline of about 110 ng/dL
every d e c a d e
 Elevation of SHBG by about 1% per year
 Total testosterone levels may b e normal ni
aging men but the free (unbound) levels
of testosterone are more reliable
indicators of biochemical reduction
 Age

 Red uce d secondary sex hair growth

Loss of muscle bulk a n d strength
Loss of bone density
Low serum testosterone levels
 Pituitary Disease

Injury to the pituitary

Tumors
Surgical trauma
Vascular injury
Autoimmune hypophysitis
Granulomatous metastatic
disease
Hemochromatosis (rare)
 Diagnosis of Hypogonadism

Circadian rhythm an d the time of sampling

must b e considered
Multiple estimation of free a n d bound
testosterone levels should b e done on
different days before a diagnosis
Clinical signs and symptoms of
hypogonadism
loss of secondary sexual characteristics,
osteoporosis
Diagnosis of Hypogonadism

 Secondary disease
 destruction of the pituitary
 FSH and/or LH levels
inappropriately normal or low
 Primary disease
 Pituitary MRI should b e done
 destruction of the testes
in young individuals
 FSH and/or LH levels
are elevated
 Diagnosis of Hypogonadism

Older individuals
Secondary or tertiary (hypothalamic)
dysfunction
Reduced hypothalamic pulse generator
frequency
Resulting in low or inappropriately normal FSH and/or LH
levels
TANNER STAGING OF GENITAL
AND PUBIC HAIR DEVELOPMENT IN
MALES
STAGES OF GENITAL
DEVELOPMENT

 1 Prepubertal
 2 Enlargement of scrotum
and testes
 3 Increased length of penis,
further enlargement of testes
 4 Enlargement of testes,
scrotum, and penis with
growth of glans; darkening of
scrotal skin
 5 Mature genitalia
TANNER STAGING OF GENITAL
AND PUBIC HAIR DEVELOPMENT IN
MALES

STAGES OF PUBIC HAIR DEVELOPMENT

 1 Lanugo-type hair (prepubertal)
 2 Dark terminal hair at base of
penis
 3 Darker terminal hair
spreading over junction of
pubes
 4 Terminal hair covering pubic
region, no spread to medial
thighs
 5 Mature stage with
horizontal distribution of
terminal hair to inner thighs
Testosterone Replacement
Therapy

 Parenteral testosterone
 Transdermal testosterone therapy
 Testosterone gel
 Buccal testosterone
 Complications of testosterone replacement
 polycythemia
 prostate enlargement
 possible growth-promoting effect on undiagnosed prostate cancer
 worsening of obstructive sleep a p n e a
 peripheral e d e m a
 gynecomastia
 Hormonal Production by the
Ovaries

Steroidogenic pathway a n d synthetic

enzymes are present in the ovaries
 Cholesterol is either synthesize d from
a c e t a t e or actively transported from the
low-density lipoprotein (LDL) particle in
blood
substrate for hormonal production
 Estrogen
Carbon-18 compounds
Principal estrogen: estradiol
Estrone a n d estriol are primarily
metabolites of intraovarian an d
extraglandular conversion
Promote breast, uterine, an d
vaginal development
 A ff e c t the skin, vascular smooth
muscles, bone cells, & central nervous
system
 Estrogen
 la c k of estrogen that natura lly o c c urs
with the onset of menopause
atrophic changes
During the reproductive period
 estrogen is responsib le for follicular phase
changes in the uterus
Deficiency
 Irregula r incomplete development of the
a nd
endometrium
PCraorbgoens-
Produced by the corpus luteum
2t1ecroomnthe
Induces peound
secretory activity of those
en do me trial g lands that have b een
p rim ed by estrogen
 Readying the endom etrium fore m bryo
implantation
Dominant hormone responsible for the luteal
phase
 Defic iency: failure of imp la ntation of the
embryo
 Progesterone

Thickening of the cervical mucus

Reduction of uterine
contractions
Thermogenic effect: basal
body temperature rises after
ovulation
 Androgens
Androstenedione
Dehydroandrostenedione
Testosterone
Dihydrotestosterone
 carbon-19 compounds

*Unlike estrogen, which is not produced in

the ovary menopause,
androgen
after ovarian c ontinues
advanced
synthesis age well into
 Androgens

 ↑ ovarian androgens in women

Excess hair growth (hirsutism)
Loss of female characteristics
 severe c ases—development of overt
m ale secondary sexual features
masculinization or virilization
Other hormones
Inhibins A and B
 Produced by the ovaries
 Inhibit FSH production

Activin
enhances FSH secretion an d induces
steroidogenesis
Folliculostatin, relaxin, follicle
regulatory protein, oocyte maturation
factor, and meiosis-inducing substance
important yet not clearly
characterized functions
 The Menstrual Cycle

 2 phases of parallel events occurring at the

ovaries a n d endometrium
Within the ovaries
follicular a n d luteal phases
Endometrial events
proliferative a n d secretory phases
 The Follicular Phase

Begins with the onset of menses a n d ends on

the day of LH surge
 Early in the follicular p hase, the ovary
secretes very little estrogen or progesterone
 Rise in FSH, however, stimulates estrogen
production
 The Follicular Phase
Estrogen secreted by the developing
follicle within the ovary stimulates:
 uterine epithelial cells
 blood vessel growth
 endometrial gland development to increase the thickness
of the endometrium

Intense secretory capacity of the uterine

glands provides a secretion that aids the
implantation of the embryo
 The Luteal
Phase
Estrogen levels peak 1 day before
ovulation, at which point a positive
feedback system results in an LH surge
Start of the luteal phase is marked by the
extrusion of the ovum approximately 36 hours
after this LH surge → luteinization of the
Graafian follicle to form the corpus luteum
Corpus luteum secretes progesterone to aid
in the implantation of the embryo
 The Luteal
Phase
In the absence of fertilization
Gradual decline in the production of
progresterone & estrogen by the corpus
luteum
Loss of endometrial blood supply
Shedding of the endometrium
approximately 14 days after
ovulation occurred
 The Luteal
Phase

Typical duration of menstrual bleeding : 3–5

days
Blood loss averaging 50 mL
Onset of menses marks the end of the
luteal phase
Hormonal Control of Ovulation

 GnRH pulse generator of the arcuate nuclei and medial preoptic

nuclei of the hypothalamus
 Positive and negative feedback responses
 Estrogen
 Progresterone
 LH
 FSH
Hormonal Control of Ovulation
REPRODUCTIVE
YEARS
AFTER MENOPAUSE  ↑ FSH levels
 Early in the follicular phase
 ↓ Estrogen
 ↑ LH
 ↑ FSH
 Midcycle surge
 ↑ LH  Stimulates a series of events
 Culminates in ovulation
 FSH ↓
 Hormonal Control of
Ovulation

Anovulation an d amenorrhea
Injury to the hypothalamus
Presence of either psychosocial or
physical stressors
Changes in hormonal cues
TANNER STAGING OF BREAST
AND PUBIC HAIR DEVELOPMENT IN
FEMALES

 STAGES OF BREAST
DEVELOPMENT
 1 Prepubertal
 2 Elevation of
breast b u d a n d
papilla, areolar
enlargement
 3 Elevation of breast
tissue an d papilla
 4 Elevation of areola a n d
papilla in secondary mound
a b ov e the level of the
breast
 5 Mature stage: recession of
areola into the breast with
projection of papilla only
TANNER STAGING OF BREAST
AND PUBIC HAIR DEVELOPMENT IN
FEMALES

 STAGES OF PUBIC HAIR

DEVELOPMENT
 1 Lanugo-type hair (prepubertal)
 2 Dark terminal hair on labia
majora
 3 Terminal hair covering labia
majora a n d spreading to the
mons pubis
 4 Terminal hair fully covering the
labia majora a n d mons pubis
 5 Terminal hair covering the labia
majora, mons pubis, a n d inner
thighs
Menstrual Cycle

Abnormalities
Am enorrhea

O lig om enorrhea

M enorrha g ia
 Amenorrhea

Absence of menses
Primary amenorrhea
Has never menstruated
Secondary amenorrhea
 A t least one menstrual cycle followed by
absences of menses for a minimum of 3–
6 months
 Oligomenorrhe
a

 Infrequent of irregular menstrual bleeding

 Cycle lengths in excess of 35–40 days
 *Menorrhagia: Uterine bleeding in excess of 7 days is dysfunctional
 Infertility: luteal phase is less than 10 days or when an
endometrial biopsy indicates the progression of endometrial
changes is delayed or out of phase, resulting in implantation
failure
 Hypogonadotropic
Hypogonadism

Gonadotropin (FSH an d LH) deficiency

Decreased sex steroid production
 C o m m o n cause of secondary
amenorrhea
 Hypogonadotropic
Hypogonadism
Physiologic and
pathologic causes:
 Weight loss
 anorexia nervosa, various
disease processes,  Any secondary cause of
chronic hypogonadism c a n
intense physical exercise induce pathologic bone
(runner’s amenorrhea) loss
 Pituitary tumors that  osteopenia
disrupt secretion of FSH  osteoporosis
or LH
 Prolactin production
by
prolactinomas
 Hypergonadotropic
Hypogonadism

 Ovarian failure resulting in elevation of FSH

concentrations with or without LH
elevations
 Occurs naturally between 45 a n d 55 years of
a g e in American women
 Depletion of oocytes a n d follicles occurs at the
expected time→ menopause
 Natural, inevitable event
 Elevation of FSH an d LH levels, with low levels of
estrogen
 Hypergonadotropic
Hypogonadism

 Premature ovarian failure

 Primary hypogonadism in a woman before the a g e of 40 and c a n
be a result of congenital chromosomal abnormality (Turner’s
syndrome) or premature menopause
 No hot flashes
 Secondary hypergonadotropic hypogonadism
 Premature menopause c a n occur in isolation or in association with
other endocrine gland failure such as hypoparathyroidism,
hypothyroidism, or hypoadrenalism
Polycystic Ovary
Syndrome
 Tests:
 Free testosterone,  Symptoms:
 SHBG,  Infertility
 FSH,  Hirsutism
 LH  Chronic anovulation
 Fasting glucose  Glucose intolerance
 Insulin  Hyperlipidemia or
 Lipid levels dyslipidemia

 Ovarian ultrasound  Hypertension

 reveals multiple cysts in  Perimenarchial onset

many patients (30% d o not  Chronic, slow progression
have ovarian cysts)
 Polycystic Ovary
Syndrome
 Most patients are overweight
 Eastern Asian or South American descent are
of normal weight
 Most symptoms a n d laboratory abnormalities
are reversed with weight loss & increased
physical activity
 Drug Glucophage (Metformin)
Normalizes menstrual cycles
Improves conception rates
Hirsutis
m

 Abnormal, abundant, androgen-sensitive terminal hair growth

in areas in which terminal hair follicles are sparsely distributed
or not normally found in women
 Idiopathic in etiology: 60% of cases
 PCOS: 35% of cases
 *Women of Italian, eastern European, eastern Indian, and Irish
descent possess more androgen-sensitive terminal hair than d o
most northern European women
 5%–10% of American women have hirsutism
 Ferriman-Gallwey Scale

 9 areas for assessment:

 1. lip chin
 2. sideburn region
 Scale of 1–4 based on
 3. neck
hair thickness &
 4. chest
 pigmentation
 5. abdom en
 Score of higher than 8 is
 6. upper back consistent with a diagnosis
of hirsutism
 7. lower back
 8. upper thigh
 9. lower thigh
Estrogen Replacement Therapy

 ↑ incidence of
invasive  ↓ bone loss
breast cancer
 ↓ colon
 ↑ venous polyp
clot formation
formation
 ↓
 no benefit in menopausal
cognitive decline symptoms
or coronary artery
 hot flashes
disease
 Vaginal
dryness
 MISCELLANEOU
S ENDOCRINE
GLANDS
KIDNEYS

PANCREA

S GASTROINTESTINAL

TRACT

PLACENT
A
KIDNEY
S
RENI
N

ERYTHRO PO IE

TIN 1,25-DIHYDROXY

VITAMIN D3

PRO STAG LAND

INS
 RENI
N

Initial component of the renin-angiotensin-

aldosterone System
Produced by the juxtaglomerular cells of the
renal medulla
Extracellular fluid volume ↓
Blood pressure ↓
ERYTHROPOIETIN
 Single-chain polypeptide
 Produced by cells close to the proximal tubules
 Production is regulated by blood oxygen levels
 Hypoxia produces increased serum concentrations within 2
hours
 Acts on the erythroid progenitor cells in the bone marrow
 Increasing the number of red blood cells
 Chronic renal insufficiency
 Erythropoietin production ↓
 Anemia
1,25-DIHYDROXY VITAMIN D3

Active form of vitamin D

Determine phosphate & calcium
balance
Bone calcification in the human body
Chronic renal insufficiency
Osteomalacia inadequate bone calcification,
the adult form of rickets
Distortion of normal
vitamin D metabolism
 PROSTAGLANDINS

 ↑ Renal blood flow

 ↑ Sodium a n d water excretion
 ↑ Renin release
Oppose renal vasoconstriction due to:
Angiotensin
Norepinephrine
PANCREAS

SECRETI
N
CHOLECYSTOKINI
N
 SECRETI
N

 Responsible for the production of bicarbonate-rich & alkaline

pancreatic fluid
 Protects the lining of the intestine from d a m a g e
 Synthesized in response to the acidic contents of the stomach
reaching the duodenum
 Affect gastrin activity in the stomach
CHOLECYSTOKININ (CCK)

Formerly called pancreozymin

In the presence of fats or amino acids in
the duodenum, is produced by the cells of
the intestinal mucosa
Responsible for release of enzymes from the
acinar cells by the pancreas into the
pancreatic fluid
GASTROINTESTINA
L
TRACT
GASTRI
N GASTRIC INHIBITORY
POLYPEPTIDE
GASTRI
N
 Most potent stimulus to gastric
secretion
 Secreted by specialized G cells in the
gastric mucosa a n d the duodenum
 In response to:
vagal stimulation
 c o n t a c t with secretagogues
 Inhibitory influences include high
gastric acidity
GASTRIC INHIBITORY
POLYPEPTIDE

Secreted by K cells in the middle a n d

distal duodenum a n d proximal jejunum
In response to food products such as:
Fats
Glucose
Amino acids
 PLACENTA
HUMAN CHORIONIC GONADOTROPIN (HCG)
HUMAN PLACENTAL LACTOGEN(HPL)
PROGESTERONE
assess a d e qu a te placental
function during the early stages of
pregnancy
HUMAN CHORIONIC
GONADOTROPIN (HCG)

 Glycoprotein hormone with two non-identical subunits (alpha

and beta polypeptide chains)
 Luteinizing hormone (LH) & Follicle-stimulating hormone (FSH)
[alpha chain]
 Produced by chorionic villi of the implanted blastocyst and
triggers the corpus luteum to release progesterone and
estrogen
 Helps maintain the uterine lining, the endometrium, with an
adequate uterine blood supply until placental synthesis of
progesterone begins
 HUMAN CHORIONIC
GONADOTROPIN (HCG)

 Detectable levels of hCG begin at about 22 days from the LMP,

which is approximately 8 to 11 days from conception
 Initially, hCG levels raise exponentially, more than doubling each
week during the first weeks in normal pregnancies
 Once progesterone is produced by the placenta to maintain uterine
function, hCG is no longer needed and the amount levels off and
declines by approximately 12 to 14 weeks’ gestation
 Chorionic gonadotropin is the most commonly measured
 Human placental lactogen

Single polypeptide chain with similarities in

structure to growth hormone
Early in pregnancy
 Regulates metabolism of maternal fats a n d glucose
Inhibiting maternal insulin
Sparing glucose for fetal metabolism

 A t the end of pregnancy

 Helps to prepare the mammary glands for lactation
 Progesterone

Steroid with 21 carbons

 M a d e by the placenta from
maternal cholesterol
Helps to maintain
the endometrium
promoting growth an d
thickening of mucosal
cells
 a d e q u a t e uterine blood supply
↓Progesterone=fetal demise

poor uterine blood supply

→resulting endometrial sloughing
Inhibits further ovarian follicle
development
 Estrio
l
Major estrogen produced by
the placenta during pregnancy
Estrone a n d estradiol are
also produced from DHEAS
Produced by the maternal &
fetal adrenal glands