Sex determination
genetic sex
autosomal chromosomes
sex chromosomes
47,XXY — Klinefelter syndrome
45,XO — Turner syndrome
45,XO/46,XY mosaicism
And now for something completely different ...
As the Interactive Fly
page on the gene Sex lethal states,
“Sex determination in the developing fly is like a one ring circus that
occasionally complicates an already exciting scene by adding a second and a third ring,
providing the audience a variety of different acts taking place at different times,
and occasionally, a choice of viewing among simultaneous events.”
gonadal sex
gonadal specificity at wk 7
sex-determining region of Y-chromosome (SRY gene), expressed as testis-determining factor (TDF)
gonadal dysgenesis 5, XY-female type (Swyer syndrome)
production of H-Y antigen, a plasma membrane protein in males only
phenotypic sex
sexual differentiation at wk 10-12
androgens induce male-type reproductive system
testosterone is the most potent
|
| |
Male |
Female |
Undifferentiated
external genitalia
|
genital tubercle
urethral folds
genital (labioscrotal) swellings
|
| genital tubercle |
glans penis |
clitoris |
| urethral folds |
penis |
labia minora |
| genital swellings |
scrotum
prepuce |
labia majora |
|
Reproductive tract
|
Wolffian ducts
Müllerian ducts
|
| Wolffian ducts |
epididymis
ductus deferens
ejaculatory duct
seminal vesicles
|
regress |
| Müllerian ducts |
regress |
oviducts
uterus
vagina
|
|
hCG stimulates fetal testis
testosterone induces development of Wolffian ducts
dihydrotestosterone (DHT) differentiates external genitalia
Müllerian-inhibiting factor cause regression of Müllerian ducts
feminization due to maternal sex hormones
sex-differentiation errors
steroidogenesis
image
by Slashme
and Mikael Häggström
androgen insensitivity syndrome (AIS)
CAIS
PAIS
gonadal dysgenesis
complete
partial
5α-reductase deficiency
testosterone biosynthetic defects
cytochrome P450,CYP11A deficiency
3-beta-hydroxysteroid dehydrogenase deficiency
cytochrome P450,CYP17 deficiency
17-ketosteroid reductase deficiency
adrenal production of dehydroepiandrosterone (DHEA)
micropenis
timing defect in 46,XY individuals
androgenital syndrome
female pseudohermaphroditism 6
precocious pseudopuberty 7
congenital adrenal hyperplasia in 46,XX individuals
SOX9 8
camptomelic dysplasia (bone and cartilage changes)
male → female sex reversal
Immunological aspects of pregnancy
endometrium as privileged site
trophoblast
only the extraembryonic trophoblast interfaces with maternal tissue
trophoblast membranes do not express polymorphic form of
class I or class II transplantation HLA antigens
some monomorphic class I antigens are found on cytotrophoblast, but no class II
trophoblast membranes are not, however, antigenically inert
both B- and T-lymphocyte activation by trophoblast antigens
early step in generation of cytotoxic reactions in cell-mediated
immunity is allogeneic recognition
blocking of allogeneic recognition by B cell-produced antibodies to
trophoblast can inhibit T cell activation
TLX (trophoblast lymphocyte cross-reactive) antigens
normal pregnancy requires maternal immunological recognition of TLX antigens
inherited by conceptus
|
|
| Factor |
Primary
aborting couple |
Childbearing
couple |
Secondary
aborting couple |
| TLX |
same as mother |
differs from mother |
differs from mother |
| blastocyst |
not recognized |
recognized |
recognized inappropriately |
| protective response |
inadequate |
present |
blastocyst
rejected |
| pregnancy |
aborted |
successful |
aborted |
|
trophoblast antigens
TA1 group
primarily protein with some carbohydrate
TA2 group (TLX)
primarily carbohydrate with some protein
With all of this information about trophoblast antigens, it is necessary to have a working hypothesis of how
these antigens might be dealt with by a normal woman’s immunologic system. Two sets of observations have
helped formulate such a working hypothesis. First is the finding that trophoblast is the only normal tissue
recognized by antibodies to TA1 (and it is exceedingly difficult to demonstrate maternal anti-TA1 in normal
pregnancies). Second is the serologic result that antibodies to TLX antigens within the TA2 group are lymphocytotoxic
(and maternal anti-TLX can be demonstrated both in normal and abnormal pregnancies). This is interpreted to mean that
TA1 is “foreign” (i.e., oncoextraembryonic) antigen and TA2 (TLX) is “self”-antigen,
and that mothers have TA2 (TLX) reactive B-lymphocytes in their repertoire. Antigen-reactive B-lymphocytes can be
activated to produce TA1-blocking antibodies by either allotypic TA2 (TLX) in seminal plasma or allogeneic trophoblast
membrane antigens during the host-versus-graft reaction subsequent to blastocyst implantation. If allotypic or
allogeneic stimulation fails to produce an adequate anti-TA2 (TLX) response, the oncoextraembryonic TA1 antigens
are recognized and rapidly rejected. If allotypic or allogeneic stimulation produces an aberrant anti-TA2 (TLX) response
(e.g., a cytotoxic rather than a blocking antibody), the extra-embryonic membranes and placenta come under
immune attack and eventually are rejected.
Ever-so-slightly modified from the PubMed©
abstract of the paper by JA McIntyre & WP Faulk,
“Trophoblast
antigens in normal and abnormal human pregnancy”, Clin Obstet Gynecol, 1986 Dec, 29(4):976–98.
An allotype is the protein product (or the result of its activity) of an allele which may be detected as an
antigen in another member of the same species.
|
|
| Fate of the blastocyst |
Maternal
TLX-1,2 |
|
Paternal
TLX-1,3 |
| 1 |
3 |
| 1 |
1,1
aborted |
1,3 |
| 2 |
2,1
aborted |
2,3 |
|
|
|
| Fate of the blastocyst for primary aborting couples |
Maternal
TLX-1,2 |
|
Paternal
TLX-1,2 |
| 1 |
2 |
| 1 |
1,1
aborted |
1,2
aborted |
| 2 |
2,1
aborted |
2,2
aborted |
|
Summary:
Together, the TA1 and TLX antigens may function in normal pregnancy by inducing
maternal production of antibodies that block the immune response to TA1. Thus, absence
of TLX antigen recognition due to sharing of maternal-paternal TLX antigen profiles may
not allow anti-TA1 activity and may lead to subsequent fetal rejection
Fertilization ...
occurs in the ampulla of the fallopian tube [oviduct]
penetration of corona radiata and zona pellucida
sperm fertilin binds with egg integrin to allow sperm to enter
species-specific
block to polyspermy
results of fertilization: the conceptus
zygote → morula → blastocyst
cytotrophoblast and syncytiotrophoblast
inner cell mass [embryoblast]
implantation
ectopic pregnancies
decidua and placentation 1
prostaglandin secretion
placenta formation
chorionic villi
umbilical vessels
... or not: Contraception
The Pill
combines synthetic estrogen and progestin
21 + 7 days
92–99.7% effective
The Mini-Pill
only synthetic progestin
28 days
87–99.7% effective
NuvaRing®
clear, flexible, thin polymer ring about 55 mm in diameter and 3 mm thick
continuous low dose of etonogestrel (0.120 mg) and ethinyl estradiol (0.015 mg)
21 + 7 days
99% effective
Yasmin®
lose-dose birth-control pill
drospirenone (3.0 mg) and ethinyl estradiol (0.030 mg)
21 + 7 days
drospirenone has antimineralocorticoid activity that influences the regulation of water retention
and electrolyte balance in the body, as well as antiandrogenic properties
prescribing information
99% effective
Natazia™
lose-dose birth-control pill
estradiol valerate and estradiol valerate/dienogest in the following regimen:
• 2 dark yellow tablets each containing 3 mg estradiol valerate
• 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest
• 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest
• 2 dark red tablets each containing 1 mg estradiol valerate
• 2 white tablets (inert)
prescribing information
effectiveness
levonorgestrel-releasing intrauterine system
Mirena®
consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir
(hormone elastomer core) around the vertical stem
prescribing information
>98% effective
extending the time between periods
levonorgestrel/ethinyl estradiol (Seasonique® and Seasonale®)
prescribing information for Seasonique®
prescribing information for Seasonale®
>99% effective
use of Seasonique® prohibited in Massachusetts and Texas and by any patient whose prescription costs are covered
in whole or in part by a federal healthcare program, such as Medicare (including Medicare Part D)
or Medicaid, or by any similar federal or state program, including a state pharmaceutical assistance program.
emergency contraceptive (morning-after) pills
Plan B® instructions: take one white pill within 120 hours after
unprotected sex and 1 more white pill 12 hours later;
each dose contains 0.75 mg levonorgestrel
89% effective
Preven®, a combined ECP, no longer marketed
RU-486 (mifepristone [Mifeprex®])
causes early medical/chemical abortion in pregnant women by blocking receptors of progesterone
must be used within 49 days of day 1 of last menstrual cycle
eligible women who choose RU-486 need to visit a specially-trained health care
provider three times for the entire procedure:
-
first, to receive a three-pill dose by mouth;
-
second, to take misoprostol, a prostaglandin, two days later; and,
-
third, to return in approximately two weeks to be certain there was a full abortion
effective in inducing a complete early abortion in 92–95% of women
Hormones in gestation
luteal hormones
estradiol
progesterone
17α-progesterone
androstenedione
decidual hormones
prolactin
insulin-like growth factor binding protein-1 (IGFBP-1)
pregnancy protein-14 (PP14)
placental steroid hormones
progesterone
17α-hydroxyprogesterone
17β-estradiol
estriol
estrone
placental peptide hormones
placental gonadotropin releasing hormone (pGnRH)
placental corticotropin releasing hormone (pCRH)
placental thyrotropin releasing hormone (pTRH)
placental pituitary-like hormones
human chorionic gonadotropin (hCG) 2
placental growth hormone (pGH)
placental adrenocorticotropic hormone (pACTH)
human chorionic somatomammotropin (hCS) [human placental lactogen (hPL)]
gestational diabetes 3
human chorionic thyrotropin (hCT)
placental growth factors
inhibin & activin
insulin-like growth factors-I and-II (IGF-I and IGF-II)
other placental peptides
pregnancy-specific β1-glycoprotein (SP1)
pregnancy-associated plasma protein-A (PAPP-A)
placental protein-5 (PP5)
fetal compartment
alpha-fetoprotein (AFP)
maternal changes
PIH/PRH
prolactin
oxytocin
Go to beginning
| Questions for thought |
| 1. |
|
List the three mechanisms that determine the sex of an individual. For each,
also describe at least one error that can interefere with the correct assignment
of sex.
|
| 2. |
|
Describe the development of the reproductive tract in the male; be sure to
include all the signals necessary to effect the changes.
|
| 3. |
|
Discuss why the trophoblast is not immunologically rejected.
|
Go to beginning
Links
- Referenced sites
- Other sites
-
How does the trophoblast protect fetal tissues from attack by maternal NK cells in the decidua? A
possible solution is offered in this article on
“Keeping Mother at Bay”
-
The effects and treatment of
prolactinomas
-
The Visible Embryo
details the changes occurring during development of the conceptus
I highly recommend
Embryo Images, for its magnificent illustrations
of normal and abnormal mammalian development
And then there is
The Multi-dimensional Human Embryo from the
University of Michigan
