Human Reproductive Biology Overview

Introduction

• Sperm develop the ability to fertilize an egg in the tail of the epididymis.
• Ejaculation releases sperm with fluids from seminal vesicles and the prostate gland.
• Prostate fluid is rich in citric acid, acid phosphatase, zinc, and magnesium ions.
• Seminal vesicle fluid is rich in fructose (energy source for sperm) and prostaglandins.
• Fertility can be achieved with as few as 25 million sperm per ejaculate.

Sperm Transport & Capacitation

• Sperm transport through the female reproductive tract begins in the vagina and ends in the uterine tube.
• Seminal fluid protects sperm from the acidic environment of the vagina.
• Rapid sperm transport (5-20 minutes) is driven by muscular movements of the female reproductive tract.
• Slow sperm transport (2-4 days) involves sperm swimming through cervical mucus, storage in cervical crypts, and final passage through the cervical canal.
• Only a few hundred sperm enter the uterine tube, typically the one containing the ovulated egg.
• In the isthmus of the uterine tube, sperm bind to the epithelium for about 24 hours to undergo capacitation.
• Capacitation involves removing cholesterol and glycoproteins from the sperm surface, preparing them for fertilization.
• Capacitation is essential for the acrosome reaction to occur.
• Hyperactivation after capacitation helps sperm break free from the tubal epithelium, penetrate mucus, corona radiata, and zona pellucida.

Fertilization

• Fertilization occurs in the ampullary portion of the uterine tube.
• Sperm penetrate the corona radiata, the outer layer surrounding the egg.
• Hyaluronidase from sperm and active sperm movement facilitate penetration.
• Sperm bind tightly to the zona pellucida via the sperm head's plasma membrane.
• Sperm specifically bind to the ZP3 molecule on the zona pellucida.
• The acrosome reaction releases enzymes from the acrosome (acrosin & serine proteinases) for penetration of the zona pellucida.
• Binding to the egg's plasma membrane occurs via the sperm's equatorial region and microvilli on the egg’s surface.
• The acrosome reaction is essential for sperm-egg fusion.

Zona Reaction & Pronucleus Formation

• The zona reaction prevents polyspermy by modifying sperm receptors on the egg's plasma membrane and releasing hydrolytic enzymes into the perivitelline space.
• Sperm entry triggers Ca++ waves in the egg, completing the second meiotic division and activating maternal RNAs.
• The sperm's chromatin loosens within the egg, forming the male pronucleus, which moves toward the egg's nuclear material.
• Histones re-associate with the male chromosomes.
• The egg completes the second meiotic division, releasing a polar body.
• The male and female pronuclei form and persist for about 10-12 hours.

Zygote Formation & Cleavage

• The male and female pronuclei organize around a mitotic spindle, derived from the sperm's centrosome.
• This marks the completion of fertilization, creating a zygote.
• Cleavage begins, leading to mitotic divisions of the zygote, creating blastomeres which become smaller with each division.

Morula & Blastocyst Formation

• Blastomeres initially form a loose cluster, then compact tightly to form a morula, held together by tight junctions.
• Compaction segregates inner cells (inner cell mass) from outer cells (outer cell mass).
• The inner cell mass forms the embryo proper, and the outer cell mass forms the trophoblast, which contributes to the placenta.
• Fluid penetrates the zona pellucida, forming the blastocele, signifying the development of a blastocyst.
• The inner cell mass becomes the embryoblast, located at one end, and the outer cell mass becomes the trophoblast, forming the blastocyst’s epithelial wall.

Embryo Hatching & Implantation

• The zona pellucida surrounding the blastocyst degenerates, allowing the blastocyst to grow.
• The blastocyst derives nourishment from uterine gland secretions.
• The loss of the zona pellucida allows implantation to begin.
• Trophoblastic cells penetrate the uterine mucosa, starting around day 6.
• Initial blastocyst attachment is mediated by L-selectin on trophoblast cells and its receptors on uterine epithelium.
• Integrins on the trophoblast then interact with laminin and fibronectin, promoting attachment and migration for implantation.
• By the end of the first week, the blastocyst is implanted in the uterine mucosa.

Epiblast, Hypoblast, & Axis Formation

• Embryoblast cells differentiate into epiblast (dorsal) and hypoblast (ventral) layers, establishing dorsal-ventral polarity.
• Hypoblast cells form the anterior visceral endoderm (AVE), which migrates to the future cranial end of the embryo.
• AVE cells secrete nodal antagonists like cerberus and lefty1, specifying the cranial end of the embryo.
• In the absence of these inhibitors, nodal signaling establishes the primitive streak at the caudal end.
• This establishes the cranial-caudal axis of the embryo during implantation (days 5.5-6).