Reproductive Physiology 2

Formation of gametes

Gametogenesis comparison 9
  Spermatogenesis Oögenesis
spermatogonia
types Ad, Ap, and B
oögonia
two mitotic divisions  
4 primary spermatocytes primary oöcyte
first meiotic division  
  8 secondary spermatocytes secondary oöcyte
first polar body
second meiotic division  
  16 spermatids mature ovum
3 second polar bodies
16 spermatozoa

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 ...



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


development of the ductal system

development of the ductal system



development of the ductal system

development of the external genitalia



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

the process of 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

More recents considerations:

Although many mechanisms have been proposed to explain fetal tolerance, further research is necessary to elucidate fully the complex net of interactions guaranteeing implantation of a ‘foreign’ fetus, its growth and normal placental development. Nevertheless, there is enough experimental and clinical evidence to conclude that both TREG and HO-1 are very important for pregnancy outcome. Future work is likely to focus on investigating their mechanisms of action and their interaction with other relevant pathways. Novel approaches such as microarray technologies may help in revealing new molecules associated with tolerance. The great advantage of the ongoing animal models of fetal tolerance is that tolerance can be achieved by manipulating early events. Understanding of theinteractions of components implicated in prevention of rejection of the fetus is essential for the design of therapies to prevent pregnancy complications such as spontaneous abortion and preeclampsia. The concept of redirecting the maternal immune system to recognise and tolerate paternal cells was introduced in the late 1970s by vaccinating mothers with cells from their partners before pregnancy; this was considered a promising treatment because blood transfusion given before transplants was reported to decrease the rejection of organ allografts. Although very controversial, this treatment has been shown to be effective in cases of immunological spontaneous abortions. It was recently reported at a scientific meeting that the treatment of patients with lymphocytes from their partners led to augmented levels of FOXP3, suggesting generation of TREG. Although speculative, the idea of using maternal TREG specific for paternal antigens as a therapy is tempting. Murine data show that it is possible to generate ex vivo antigen-specific cells with suppressor activity. Whether this therapy is an applicable one remains to be discussed in the light of ethical and safety issues.
Ana Claudia Zenclussen, Anne Schumacher, Maria Laura Zenclussen, PaulWafula and Hans-Dieter Volk (2007) Immunology of pregnancy: cellular mechanisms allowing fetal survival within the maternal uterus. Expert Rev. Mol. Med. Vol. 9, Issue 10, April 2007, DOI: 10.1017/S1462399407000294

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:

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

Hormones in lactation 4

PIH/PRH

prolactin

oxytocin


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.

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