WS
Sex Steroid Pharm
1. What kind of hormones are LH and FSH (and do you remember what the
other hormones in this category are)?
LH and FSH are peptide hormones produced by the anterior pituitary.
Another important peptide hormone is hCG (human Chorionic
Gonadotropin) produced by the placenta in a pregnancy. Other peptide
hormones include insulin, glucagon, PTH, and those secreted by the
posterior pituitary.
Where is their receptor found, on the membrane or intracellular? What
kind of signaling pathway does it use?
The receptors for peptide hormones are found on the cell membrane. They
use secondary messengers to transduce signals.
What does this mean in terms of speed of action? Are the hormones
hydrophobic or hydrophilic?
The use of secondary messengers means that peptide hormones have a fast
speed of action. Peptide hormones are hydrophilic, which means they can
freely circulate in the blood.
2. What stimulates LH and FSH to release? Where does it come from, and
how is it released?
LH and FSH are stimulated by GnRH (Gonadotropin-releasing hormone) from
the hypothalamus. GnRH is secreted in a pulsatile fashion; the rhythm of the
pulses indicates how much LH and FSH should be released.
3. How are steroid hormones different from peptide hormones?
Steroid hormones VS. peptide hormones:
● They are synthesized from cholesterol.
● They are released immediately after synthesis.
● They are lipophilic and require carrier proteins to travel in the blood.
● They bind to intracellular receptors.
● They alter gene expression.
● They are slower in onset but longer in duration.
4. What are the 3 families of sex steroids?
The 3 categories of sex steroids are:
● Progestogens (21 carbons)
● Androgens (19 carbons)
● Estrogens (18 carbons)
5. What starting molecule are all sex steroids synthesized from?
All sex steroids are synthesized from cholesterol.
6. What family do all sex steroids pass through on the way to their final
chemical destination?
All sex steroids pass through progestogens on the way to their final chemical
destination.
7. How do these hydrophobic sex steroids travel through the blood?
Since they are hydrophobic, sex steroids must bind to carrier proteins to
travel through the blood.
8. What are the 2 ways steroids can interact with a cell? Which one is
predominant?
Steroids can interact with a cell through the classical/genomic pathway or
the nonclassical/non-genomic cell membrane pathway. The
classical/genomic pathway is the predominant pathway.
9. What are the main natural roles of the progestogens?
Support pregnancy and to be involved in mammary gland development.
10. What is the highlighted role of the synthetic progestins?
Contraception. Progestins are also used in hormone therapy to help prevent
preterm birth and treat gynecological disorders.
11. What is the estrogen that is predominant in ovulating women?
Estradiol is the predominant estrogen in ovulating women.
Does estrogen create the same response in all tissues? How about the
medications that imitate or block it?
No, estrogen can create different responses in different tissues. An example
is Tamoxifen, which acts as an antagonist in breast tissue but in the uterus, it
is an estrogen agonist and can cause uterine cancer.
12. In addition to modulating the steroid receptors with agonists and
antagonists, what is another target of medications that impact steroid
effects?
Another target is the enzymes involved in the biosynthesis of steroid
hormones.
13. What is one other pharmacologic target to manipulate sex hormone
levels? How do these medications work? What is the potential dental
impact of these medications?
Another pharmacologic target is GnRH manipulation.
GnRH agents work by changing the GnRH pulsatility pattern or by acting as
direct antagonists. This can alter the release of LH and FSH, which in turn
affects the production of sex steroids. Used for reproductive tech (slide 33).
The potential dental impact of these medications is osteoporosis, which can
affect the mandibular bone density.
Physiology of Sexual Development
1. Is sex determined only by chromosomes in all animals?
No, sex is not determined only by chromosomes in all animals, some are by
temperature.
2. The first step of sex differentiation is gonadal
development (gonadogenesis). For the testes to
develop from the multipotent gonadal cells, what must
be present?
The SRY gene must be present for the testes to develop.
For the ovaries to develop from this same type of cells,
what must be present?
The SRY gene must be absent, and ovary-inducing genes
(e.g., WNT4 and R-Sponidin 1 (RSPO1)) along with testis-
suppressing genes (e.g., FOXL2) must be present.
3. What are the two “ducts” of the undifferentiated embryo?
Wolffian duct and the Müllerian duct.
4. Which one becomes the male internal organs if development is
typical?
The Wolffian duct.
5. Which one becomes the female internal organs if development is
typical?
The Müllerian duct.
6. What hormone is necessary for the Wolffian ducts to develop into male
internal organs, and where does it typically come from?
Testosterone; fetal testes.
7. What hormone is necessary for the Mullerian ducts to regress in the
male, and where does it come from?
Anti-Mullerian hormone (AMH); Sertoli cells of the fetal testis.
8. What does the development of female external genitalia depend on?
The development of female external genitalia depends on the absence of
exposure to androgenic hormones such as testosterone and DHT. It does not
depend on a hormone or chromosomes.
9. Are sex and gender the same? No..?
XX DSDs
1. What is the most common sex chromosome aneuploidy in living
persons?
45, X, aka Turner syndrome.
2. What happens to 45 X gonads?
In 45, X individuals, the gonads initially differentiate into ovaries, but
after 3 months gestation, accelerated apoptosis of the oocyte leads to
the degeneration of the ovary to streaks of fibroblastic tissue with
few (if any) oogonia. This is also known as streak gonads.
3. What are some ways an XX embryo/fetus can have androgen
excess exposure?
○ Maternal sources: Virilizing ovarian or adrenal tumor, or luteoma
of pregnancy.
○ Fetal sources: Congenital adrenal hyperplasia (CAH).
○ Iatrogenic/exogenous: Exposure to testosterone and related
steroids, certain synthetic oral progestins, and rarely stillbestrol
(DES).
4. CAH is relatively common - but there are numerous forms based on
which enzyme is deficient. CAH is often handled as simply an
“endocrine disorder” even though there are often also sex
development differences. Be aware of your patient’s comfort in
talking about this disorder (you will likely have some patients with
it). Know that there are some forms of CAH that are life-
threatening at birth. How is it inherited?
Autosomal recessive manner.
5. Why does CAH make atypical external genitalia in the XX infant
but not in the XY infant?
CAH can cause atypical external genitalia in XX infants because it leads
to an excess of androgens, which can masculinize the internal ducts
and/or external genitalia.
In XX infants, this can lead to the development of atypical genitalia,
such as labioscrotal fusion or clitoromegaly.
In XY infants, the excess androgens do not cause the same atypical
development of the external genitalia because the genitalia are already
being masculinized by the presence of the SRY gene on the Y
chromosome. Instead, the excess androgens may cause features such
as enlarged genitalia or early puberty.
XY DSDs
1. What is 47 XXY commonly called? Do they form testes and explain
why/why not?
47 XXY is commonly called Klinefelter syndrome.
Yes, they form testes because the SRY gene is present.
Do they develop typical male internal and external genitalia?
However, in what hormone do they have an insufficiency compared
with 46 XY persons?
Yes, they develop typical male internal and external genitalia BUT have
a testosterone insufficiency compared with 46 XY persons.
2. In the Androgen Biosynthesis Disorder category, be familiar with
5α-reductase deficiency. Which step in the sex development is
affected?
5α-reductase deficiency affects the conversion of testosterone to
dihydrotestosterone (DHT).
3. Be familiar with Androgen Insensitivity Syndrome. What phenotype
will these people have and why?
Androgen Insensitivity Syndrome (AIS) is when an individual has an XY
karyotype but has a problem with the androgen receptor.
○ Step 1: SRY is present, leading to testes formation.
○ Step 2: Testes produce AMH and testosterone, but the
testosterone cannot act due to the faulty receptor.
○ Step 3: AMH causes the Müllerian ducts to regress, but the
Wolffian ducts do not develop into male internal organs. The
lack of testosterone action leads to female external genitalia.
4. Be familiar with Swyer Syndrome (Complete Gonadal Dysgenesis).
What does the word “dysgenesis” mean? How do these people
develop? And what sex chromosomes do they have?
Dysgenesis means defective or abnormal development of an organ.
Swyer Syndrome is characterized by a mutation in the SRY gene, even
though the person has an XY karyotype. The lack of a functional SRY
gene leads to the development of female internal and external
genitalia.
External
Internal
Disorder Karyotype Gonads Genitali Hormones Characteristics
Genitalia
a
Most common sex
chromosome aneuploidy;
47, XXY (most Testosterone SRY, AMH, testosterone,
Klinefelter common); also 48, Testes Typical insufficiency DHT present and functioning;
Typical male male compared to
Syndrome XXXY, 48, XXYY, (small) No Müllerian ducts; May
46, XY
49, XXXXY have breast development,
small testes, poor beard
growth, and osteoporosis.
Most common sex
chromosome aneuploidy in
living persons; Gonads
45, X (most initially differentiate into
common); also Streak No ovarian ovaries but degenerate due
Turner gonads Typical Typical hormones
45,X/46,XX or female
to accelerated apoptosis of
Syndrome (dysfunctional female (estrogen,
45,X/46,XY ovaries) progesterone) oocytes; No SRY,
mosaicism testosterone, AMH, or DHT;
May have short stature,
webbed neck, and other
physical features.
Excess Most common form of 46, XX
androgens
(testosterone)
DSD; Autosomal recessive
Congenital
due to inheritance; Can lead to
Adrenal Typical Ambiguous
46, XX Ovaries
(virilized)
enzyme labioscrotal fusion or
Hyperplasia female deficiency in clitoromegaly; Requires
(CAH) cortisol
synthesis
lifelong hormone
pathway replacement therapy.
Absent or Second most common cause
underdeveloped of primary amenorrhea;
Müllerian Normal
Müllerian
Typical female Possibly linked to WNT4
Agenesis 46, XX Ovaries structures
female hormone
(uterus, fallopian mutations; IVF and
(Dysgenesis) levels
tubes, cervix, gestational carrier may be
upper vagina) options for genetic offspring.
Affects conversion of
Ambiguo testosterone to DHT; At birth,
us at Testosterone may have female or ambiguous
5α-reductase
46, XY Testes Typical male birth, present, DHT external genitalia; At puberty,
deficiency virilization deficient increased testosterone levels
at puberty lead to masculinization of
external genitalia.
Testostero X-linked recessive
Androgen
Testes No Müllerian ne inheritance; Testes present
Insensitivity Typical
46, XY (undesc or Wolffian present, but cannot respond to
Syndrome female
ended) structures but androgens; AMH present, so
(AIS)
androgen Müllerian ducts regress; No
Wolffian duct development;
At puberty, testes secrete
receptor
testosterone, which is
dysfunctio
aromatized to estrogen,
nal
leading to breast
development.
Mutation in SRY gene; No
No testicular or ovarian
Swyer testosteron development; Müllerian
Syndrome Streak Typical Typical
46, XY e, no structures develop; Female
(Complete Gonadal gonads female female
Dysgenesis) AMH, no external genitalia; Requires
DHT hormone replacement
therapy at puberty.
