Somatic cells

• Most of the body’s cells
• Diploid (2n) : 46 chromosomes

Reproductive cells: gametes

• Sperm and egg cells
• Haploid (1n): 23 chromosomes

INTERPHASE

• Cell doubles in size and DNA during interphase
• 90-95% of cell cycle
• G1: cell grows without replicating DNA
• S: synthesis phase, DNA replicates
• G2: cell synthesizes proteins in preparation for mitosis
• Chromosomes condensed during mitosis: uncondensed (chromatin form) for rest of cell cycle

MITOSIS

• Somatic cell division

Prophase

• Centrosomes migrate to opposite sides of cell
• Mitotic spindles form from centrosomes

Prometaphase

• Nuclear envelope fragments
• Nucleolus disappears
• Sister chromatids attached to each other at their centromeres until anaphase

Metaphase

• Chromosomes line up at metaphase plate

Anaphase

• Sister chromatids move to opposite sides of cell

Telophase

• Nuclear envelope reforms

Cytokinesis

• Cytoplasm divides cell into two
• Produces 2 diploid daughter cells with identical genomes

Mitosis

• Division of nucleus into 2 daughter nuclei

Cytokinesis

• Division of cytoplasm

CLINICAL CORRELATION

Aneuploidy

• Sister chromatids do not separate properly during cell division (mostly meiosis but also occurs during mitosis)
• Daughter cells with extra or missing chromosome
• Common in cancer cells

STRUCTURES AND FUNCTIONS OF THE MATURE PLACENTA, BEGINNING IN WEEK 9

• The human placenta is hemochorial; that is, it allows direct contact between maternal blood and fetal tissues. As we’ll see, chorionic villi provide the surfaces for exchange of materials, and, therefore, are the functional units of the placenta.
• Because fetal growth is dependent upon sufficient oxygen, nutrients, and other substances provided in the maternal blood, insufficient vascular remodeling has major clinical consequences, including fetal growth restriction, eclampsia, and even spontaneous abortion.
• Derived from both maternal and offspring tissues.

Week 9

Differential growth and regression of the chorionic villi initiates formation of the mature placenta.

Key Structures:

• Embryo is suspended within the amniotic cavity, which is bound by the amniotic membrane.
• Chorion plate:
  • Chorion Frondosum grows thick with villi at the embryonic pole.
  • Chorion Laeve is the thinner area, where the villi regress.
  • Chorionic Cavity surrounds the amniotic cavity and embryo.
• Endometrium -> Decidua:
  Its regions are named according to their location in reference to the embryo:
  • Decidua basalis, which comprises the decidua adjacent to the chorion frondosum.
  • Decidua capsularis, which comprises the decidua encapsulating the embryo.
  • Decidua parietalis, which comprises the decidua of the uterine wall opposite the embryo.

Week 20

Expansion of the embryo pushes these layers against each other, leading to fusion and the formation of the mature placenta; a mucous plug blocks the cervical opening.

Embryonic Pole:

• Placenta comprises fused chorion frondosum and decidua basalis.

Abembryonic Pole:

• Chorion laeve is greatly reduced, and fused with the amniotic membrane.
• Decidua capsularis has regressed (due to expansion of the embryo).
• Decidua parietalis fuses with the chorion laeve.

Placental anatomy

Growth of the fetus is driven by dynamic interactions between the mother and fetus. In healthy pregnancies, both fetal and maternal needs are met by physiological processes that operate for mutual benefit. However, when maternal health is poor, physiological compromises are made that put the mother and/or fetus at greater risk.
The placenta serves as an interface between maternal and fetal environments.

• Fetal Side
  • Amniotic membrane gives the surface a smooth, shiny appearance.
  • Umbilical cord extends from the placenta to the fetus; holds umbilical arteries and vein.
  • Chorionic plate that gives rise to the chorionic villi (specifically, to the stem villi, which then give rise to branches). “Anchoring villi,” make contact with the decidua; “floating” villi do not.
  • Fetal blood vessels travel through the umbilical cord and within the chorionic plate to reach the villi.
• Maternal Side
  • Decidual, aka, basal plate forms septa, which demarcate cotyledons; cotyledons give the maternal surface of the placenta a bumpy appearance.
• Intervillous Space
  -The space between the chorion and decidual plate.
  • Maternal vasculature passes through the decidua and opens to the intervillous space; spiral arteries, which have a cork-screw like appearance, provide the arterial blood supply to the intervillous space.

Recall that the intervillous spaces are derived from connections formed between the synctiotrophoblast and maternal sinusoids during early embryonic development.

• Transfer of materials occurs across the villous surface:
  Materials leave the maternal blood, enter the intervillous space, cross the villous surface, and then enter the fetal vessels.
  Wastes, etc. exit the fetal blood, cross the villous surface, enter the intervillous space, and enter the maternal veins.

Placental Physiologic Roles

The placenta is a temporary multi-functional organ; it performs many tasks that are taken over by various organ systems after birth.
Exchange of materials occurs in both directions across the placenta:

• From the maternal side, oxygen, nutrients, hormones, antibodies, and some drugs enter the fetal circulation.
• From the fetal side, carbon dioxide and other metabolic wastes, hormones, and red blood cell antigens enter the maternal circulation.
  Another important role of the placenta is hormone production, including:
• Human chorionic growth hormone, estrogen, and progesterone, all of which are necessary for maintenance of the decidua and, therefore, the pregnancy.
• Placental lactogen and growth hormone, which induce maternal insulin resistance later in pregnancy. By inducing insulin resistance, these hormones ensure that maternal nutrients are readily available for fetal growth.

Placental Blood Barrier

The placenta prohibits passage of many pathogens from the mother to the fetus.

• However, there are several important exceptions to this rule, which can be summed up with the TORCH rule:
  Toxoplasmosis, Others, Rubella, Cytomegalovirus, and Herpes simplex can all traverse the placenta.
  • TORCHeS
• The Zika virus is an example of a TORCHeS exception: as you are probably aware, the Zika virus can be transmitted from an infected mother to a developing offspring, resulting in serious birth defects, including microcephaly. Current research is focused on preventing its transmission across the placenta, thereby avoiding fetal infection.

PLACENTA

• The mulit-functional organ that ensures nutrient and gas exchange between maternal and offspring circulation.
• Weeks 2-8
  • Trophoblast differentiation: during implantation, the trophoblast gives rise to the cytotrophoblast and synctiotrophoblast; these layers are pivotal in establishing the fetal side of the placenta.
  • In week 2, the extra-embryonic mesodermal layers arise.
  • The first trimester is relatively hypoxic; though the synctiotrophoblast makes contact with maternal sinusoids, it also plugs maternal vessels to protect the embryo from high levels of oxygen in maternal blood, which is thought to be toxic to early developmental processes.

EVENTS OF WEEK 2

• Includes the final stages of implantation.
  • Fibrin coagulum seals endometrium at implantation site.

Embryonic Tissues of Day 9

• The outermost multi-nucleated synctiotrophoblast, which features spaces, called lacunae.
• Deep to this, is the cytotrophoblast; it comprises a single cell layer.

Recall that the cytotrophoblast and synctiotrophoblast are derived from the trophoblast layer of the blastocyst (more specifically, the trophoblast gave rise to cytotrophoblast cells, some of which then differentiated to form the synctiotrophoblast).

• Bilaminar embryonic disc:
  • The epiblast, which has ectodermal origins, and comprises columnar cells.
  • The hypoblast, which comprises cuboidal cells; because of its endodermal origins, it is also referred to as the primitive endoderm.
• Exocoelomic membrane and cavity
  • Cells from the hypoblast migrate to form the exocoelomic membrane (aka, Heuser’s membrane), which encloses the exocoelomic cavity (aka, primary yolk sac).

Embryonic Tissues of Day 12

• Synctiotrophoblast lacunae make contact with maternal sinusoids.
• Extraembryonic mesoderm separates the exocoelomic membrane and cytotrophoblast.
  • It is thought that this mesodermal tissue originates from the hypoblast, and, perhaps, the trophoblast.
  • The extraembryonic mesoderm closest to the cytotrophoblast comprises the somatic mesoderm.
  • The extraembryonic mesoderm surrounding the exocoelomic membrane is the splanchic mesoderm.
  • Spaces form within the mesoderm; these spaces become continuous to form a true separation between the splanchnic and somatic mesodermal layers.

Embryonic Tissues of Day 13

• Endometrium is healed, fibrin coagulum gone.
• Synctiotrophoblast is greatly expanded into the uterine wall and formed extensive connections with the maternal blood supply.
• The cytotrophoblast begins to transform: it gives rise to primary villi, which extend into the synctiotrophoblast.

As we’ll see, these villi become the functional sites of gas exchange between the mother and fetus.

• Extraembryonic mesoderm:
  • The outer somatic layer of extraembryonic mesoderm is adjacent to the cytotrophoblast.
  • The inner splanchnic layer surrounds the embryo proper.
  • The space between them is the chorionic cavity.
  • Mesodermal connecting stalk joins the two mesodermal layers and suspends the embryo within the chorionic cavity.

This connection will later become the umbilical cord, which carries the umbilical vessels.

• Bilaminar embryo:
  • Epiblast surrounds the amniotic cavity.
  • Primary yolk sac has regressed; the secondary yolk sac now faces the hypoblast.

End of Week 3

By the end of week three, dramatic transformations re-organize these tissues.

• Cells of the cytotrophoblast layer migrated to form the outer cytotrophoblast shell.
• Synctiotrophoblast lacunae are filled with blood from the maternal sinusoids; notice that cytotrophoblast cells surround them.
• Somatic extraembryonic mesoderm has infiltrated the cytotrophoblastic primary villi, and begins to develop embryonic vasculature -> Tertiary Villi
• Thus, the blood-filled lacunae now fill the intervillous spaces(spaces between the tertiary villi).
• Somatic mesoderm gives rise to the chorionic plate, which surrounds the chorionic cavity.

Be aware that we’ve skipped some transitional events that occurred earlier during week 3 (for example, the transition from primary to secondary and secondary to tertiary villi).

Vascular Remodeling & Tertiary Villi

During weeks 4-8, the overall organization of embryonic tissues remains as it is at the end of week 3.
However, extensive vascular remodeling lays the groundwork for the mature placenta.

• Chorionic plate gives rise to the mesodermal cores and blood vessels of the tertiary villi.
• Cytotrophoblast covers the mesodermal core of the tertiary villi, and, also, forms the outer cytotrophoblast shell; cellular columns connect outer shell and tertiary villi.
• Synctiotrophoblast lines the cytotrophoblast of the villi.
• Intervillous spaces are continuous with maternal blood vessels, and lined by synctiotrophoblast.
• As we learn elsewhere, these villi are the sites of gas, nutrient, and waste exchange between the maternal and fetal environments.

Cleavage

Mitotic division that occurs in the uterine tube.

Implantation

Endometrial encapsulation that occurs within the uterus.

• Endometrium comprises multiple layers, and, under direction from the ovarian hormones, cyclically prepares for implantation of an embryo. In the absence of implantation, the endometrial lining is shed during menstruation.

CLEAVAGE

• Zygote divides and develops to form the blastocyst during passage through the uterine tube.
• Involves multiple rounds of mitotic division without growth in size.

Key Steps:

• Zygote, single cell, produced by fusion of the male and female gametes in fertilization.
  • Has zona pellucida, which is the acellular protective coat.
• After a single round of mitosis, the zygote gives rise to two cells, aka, blastomeres.
• By the four-cell stage, the blastomeres are loosely organized, with incomplete contact between the cells.
• This changes at the 8-cell stage, when compaction reorganizes the cells and forms:
  • An inner cell mass, which is held together by tight junctions.
  • An outer cell mass, which is covered by the zona pellucida.

In the histological sample, notice the tightly packed cells and thick outer zona pellucida.

• In the next stage the morula comprises approximately 16 cells.
  • Sodium-potassium pumps are responsible for pulling water into the morula cell mass.
  • As a result, cavitation occurs
• Morula gives rise to the blastocyst, with a blastocyst cavity (blastocoel)
• Blastocyst:
  • Zona pellucida surrounds two cell populations:
    Outer cell population is now called the trophoblast.
    Inner cell mass, which has become concentrated to one side, is now called the embryoblast.

As we learn elsewhere, the trophoblast plays an essential role in implantation and formation of the placenta, and the embryoblast gives rise to the tissues of the embryo proper.

• Cavitation establishes embryonic polarity:
  • Embryonic pole at the side of the embryoblast.
  • Abembryonic pole at the opposite side.

IMPLANTATION

• Process that results in the encapsulation of the embryo within the uterine wall.
• Typically occurs after the blastocyst reaches the uterine cavity.
• It requires extensive cross-talk between the embryo and endometrium.
• Implantation window:
  • The days of the cycle when the endometrium is receptive to implantation.
  • The window typically begins 6-8 days after ovulation, and lasts approximately 4 days.
    Prior to the implantation window, the endometrial lining is thinner and has not yet released pro-embryo secretions; after this window, the endometrial lining prepares for shedding during menstruation.

We show implantation in 4 key steps:

1. Pre-implantation events, which include “hatching” of the blastocyst from the zona pellucida.
2. Blastocyst apposition to the uterine wall.
3. Early adhesion to uterine epithelia.
4. Uterine stroma – embryo contact, which ultimately connects the maternal vascular supply to the embryo.

Step 1

• In response to ovarian hormones, the stroma has undergone decidualization, and is edematous, vascularized, and rich in mucus and glycogen.
  • Thus, the endometrium is ready to house and nourish an embryo.
• The blastocyst emerges from the zona pellucida (aka, it “hatches”).
  • It can now interact directly with the maternal environment, and does so by releasing substances that prevent its rejection.
  • One of these substances, human chorionic growth hormone (hCG), preserves the corpus luteum within the ovary; recall that the corpus luteum produces progesterone, which is necessary for maintenance of the endometrial lining, and, therefore, the survival of the embryo.
    Thus, many early pregnancy tests rely on the presence of hCG to determine pregnancy status.

Step 2

Apposition involves alignment of the embryonic pole to the uterine wall, to which it loosely attaches.

• The blastocyst rolls over its surface (some texts specify that it is the inner cell mass that “rolls” within the trophoblast).
• Proper alignment relies on signaling between the epithelia and embryo: pinopods, aka, uterodomes, on the uterine wall interact with microvilli on the blastocyst and establish a loose connection.

Step 3

• Receptor-ligand signaling facilitates initial adhesion of the blastocyst to the epithelia. More specifically, chemokine reactions appear to play a significant role.

Step 4

• The trophoblast transforms as the embryo begins to sink into the endometrial stroma.
  • The trophoblast gives rise to the cytotrophoblast and synctiotrophoblast, which we show in shades of green and blue.
• The syncytiotrophoblast produces proteolytic enzymes and other substances that interact with the uterine stroma to facilitate implantation.
• The endometrial stroma plays an active role in this process, as recent research indicates that stromal cells are highly motile, and move around the embryo to envelop it.
• As part of this process, extensive vascular remodeling of the stroma allows maternal oxygen and nutrients to reach the developing embryo. Elsewhere, we’ll learn how embryonic and maternal tissues transform to produce the multi-functional placenta.

Implantation Failure

• More than half of all conceptions are spontaneously aborted.
  • In many cases, this is because of embryonic chromosomal abnormalities: blastocysts that fail to produce hCG, for example, are rejected by the maternal environment. In this way, the endometrium acts as a “bio-sensor” that detects when an embryo is of poor quality and rejects it as a way to prevent investment in offspring that are unlikely to survive.
  • In other cases, the endometrium is unreceptive because of increased inflammation, hormonal abnormalities, or other health issues.
• Ectopic pregnancies occur when implantation occurs outside of the uterus.
  • Occurs in 1-2% of all pregnancies.
  • Often occurs in the uterine tube when blastocyst transport is impaired.
  • Can also occur within the abdominopelvic cavity.
  • An ectopic pregnancy poses serious danger to the woman, particularly because its rupture leads to internal bleeding.

OVARIAN CYCLE

• Process of follicular growth and selection for ovulation.

Key events prior to ovulation

1. Primordial follicle

• Comprises a single oocyte encircled by flat granulosa cells; the ovary comprises hundreds of these units at any given time.
  • Some of these primordial follicles will enter meiosis and become primary follicles.

2. Primary follicle

• Primary oocyte, zona pellucida, and single layer of cuboidal granulosa cells.

3. Secondary follicle

• Several layers of granulosa cells surround the primary oocyte in a secondary follicle; thecal cells begin to differentiate and lie at the periphery of the follicle.

4. Follicle-stimulating hormone (FSH)

• Released by the anterior pituitary gland
• Facilitates transition of secondary follicles to the next stage

5. Early tertiary stage
   Aka, antral stage.

• Antrum forms
• Large primary oocyte.
  • As the follicle grows, it produces increasing quantities of estrogen.

6. Estrogen

• Above a given threshold, estrogen triggers the release of luteinizing hormone (LH), from the anterior pituitary gland.

7. LH “surge”

• Induces morphological and physiological changes in preparation for ovulation, including completion of meiosis I and entry into meiosis II.

8. Late tertiary follicle

• Secondary oocyte and its polar body are the products of meiosis I.
• Granulosa cells form the cumulus oophorus; this “cloud” of cells surrounding the oocyte travels with the oocyte after ovulation.
• The corona radiata comprises the granulosa cells immediately surrounding the zona pellucida.
• Two layers of thecal cells: the internal layer, which has endocrine functions, and, the external layer, which forms the follicular capsule.

9. Ovulation

• The oocyte complex, which comprises the oocyte and cumulus cells, leaves the ovary and enters the uterine tube, where fertilization may occur.
• The follicular cells that remain in the ovary transform to become the corpus luteum (“yellow body”).
  • The corpus luteum is a temporary endocrine gland: it produces progesterone, which acts on the endometrial lining to prepare it for implantation in the case of fertilization.

THE UTERINE CYCLE

• Process of uterine preparation for implantation in the event of fertilization.
• The cycle is marked by two key events:
  • Menstruation, during which the top layer of the endometrium is shed.
  • Ovulation, which is when the oocyte complex exits the ovary.

1 Uterine Cycle

1. Begins with onset of menstruation.

2. As FSH induces growth of the ovarian follicles, they produce increasing quantities of estrogen.

3. In turn, estrogen promotes the growth, aka, proliferation, of the endometrium, specifically, of the stratum functionalis (functional layer).

• Thus, this phase of high estrogen concentrations and endometrial growth following menstruation is the proliferative phase (notice that it correlates with the follicular phase of the ovarian cycle).

4. Increasing levels of estrogen trigger the LH surge that induces ovulation.

5. After ovulation, the corpus luteum secretes progesterone:

• Thus, the secretory phase of the uterine cycle begins (which correlates with the luteal phase of the ovarian cycle).
• In this phase, progesterone promotes the differentiation and decidualization of the stratum functionalis so that it becomes rich in glands and vasculature.

6. At this point, we must consider the fate of the oocyte:

• If fertilized, it will become a zygote, then an embryo.
• If not fertilized, the oocyte will degenerate within ~24 hours of ovulation.
• The “fertile window” refers to the days of the menstrual cycle when intercourse is most likely to lead to conception.
  • Research indicates that the window comprises the 5 days before and the day of ovulation;
  • However, the timing of ovulation is highly unpredictable, as it varies greatly even in women with regular menstrual cycles. Thus, family planning methods that attempt to predict the fertile window have high failure rates (~24%, according to the CDC*).

7. Regardless of its fertilization status, the oocyte (or embryo) reaches the uterine cavity in 3-4 days.

8. Again, its fate determines the events of the uterine cycle:

• If an embryo successfully implants in the endometrial lining, the corpus luteum persists to produce progesterone, which is necessary for endometrial maintenance (until the placenta can take over this role).
• If implantation does not occur, the corpus luteum regresses; it becomes the corpus albicans (“white body”) and progesterone levels fall sharply.

9. In the absence of progesterone, the stratum functionalis breaks down and is shed during menstruation, which marks the beginning of the next menstrual cycle.

OOCYTE TRANSPORT TO UTERINE CAVITY:

• Takes ~3-4 days

Female Reproductive Tract

• Upper vagina, cervix, uterus, and uterine tubes
  • Endometrial lining of the uterine cavity
  • Key features of the uterine tube: the isthmus, ampulla (the widest part of the tube), and the finger-like fimbriae.
  • Uterine tube wall comprises smooth skeletal muscle and mucosal projections, which feature ciliated epithelia.

Key events:

• Ovulation leads to two key events:
  • Expulsion of the oocyte complex and formation of the corpus luteum.
  • Oocyte complex: secondary oocyte, which is arrested in meiosis II; the zona pellucida, which is the oocyte’s acellular protective coating; the cumulus oophorus, which comprises follicular cells.
• Uterine fimbriae “sweep” the oocyte complex into the uterine tube, where peristaltic smooth muscle contractions move the oocyte towards the uterine cavity.
• In the ampulla of the uterine tube, the oocyte might encounter sperm.
  • If not, the oocyte complex degenerates within 24 hours.
  • If the oocyte and sperm meet, fertilization may occur.

SPERM TRANSPORT TO AMPULLA

• Semen comprises 100s of millions of sperm cells, which contribute less than 10% of total semen volume; the other 90% comprises protective seminal fluids and nutrients.
• Up to 10% of sperm are malformed; if malformation affects more than 20%, fertility may be impaired.

Transport through the male reproductive tract:

• Sperm form within seminiferous tubules of the testes.
• Enter epididymis, where sperm are stored for several weeks and acquire motility.
• During the emission phase, sperm and testicular fluids are transported to the ductus deferens (aka, vas deferens), which is a long muscular tube that, via peristaltic contractions, transports the sperm to the ejaculatory duct.
• Within ejaculatory duct, sperm are joined by secretions from the seminal vesicles and prostate gland before exiting the body via the urethra.

Transport through female reproductive tract:

Of the millions of sperm present in the initial ejaculate, only a portion of these will reach the ampulla; many will die within the female reproductive tract.

• Contractions of the vagina and uterus move the sperm towards the cervix.
• At the cervix, cervical mucus secreted by the cervical glands regulates passage into uterus:
  • The composition of the mucus barrier changes according to ovulatory status, so that passage is only possible during the fertile window.
  • In the days prior to ovulation, estrogen facilitates formation of watery mucus, which permits sperm passage;
  • After ovulation, progesterone alters mucus composition: it becomes viscous and, thus, impenetrable.

• Within the uterine cavity, sperm are ushered towards the oocyte complex by uterine contractions and sperm “swimming” movements; interestingly, sperm tend to move towards the side where the oocyte was released, which may imply chemical signaling between the sperm and oocyte complex.

• In the isthmus region of the uterine tube, epithelial cells bind the sperm, holding them here for approximately 24 hours.
  • During this time, tubal secretions induce sperm cell capacitation, which removes glycoproteins from the cell surface that would otherwise inhibit fertilization.
  • Then, the sperm enters a period of hyperactivity, and frees itself from the tubal epithelia. Hyperactivity is characterized by asymmetrical flagellar motions that move the sperm cell nonlinearly.

• Finally, the sperm reach the ampulla, where fertilization may occur.

FERTILIZATION

• Fusion of male and female gametes.
• Occurs within 24 hours of ovulation, after which the oocyte degenerates.

• Step 1: Sperm cells pass through the cumulus oophorus.

• Step 2: Glycoproteins on the zona pellucida bind receptors on the sperm cell that were exposed during capacitation.
  • Binding initiates the cascade of events called the acrosome reaction, in which the acrosome of the sperm cell releases enzymes that dissolve the zona pellucida;
  • Dissolution allows the hyperactive sperm cell to wiggle through the zona pellucida.

• Step 3: The sperm and oocyte cell membranes fuse, and are bound by oocyte microvilli;
  • The contents of the sperm cell move into the oocyte (the sperm cell’s plasma membrane remains outside of the oocyte).

• Step 4: The cortical reaction hardens the glycoproteins on the zona pellucida, which blocks additional sperm cells from binding with the oocyte.

• Step 5: The oocyte completes the second meiotic division, which produces the haploid oocyte and second polar body (both the cortical reaction and resumption of meiosis II are initiated by a rise in intercellular calcium, which was induced by fusion with the sperm cell).
  • The oocyte chromosomes decondense and form the female haploid pronucleus.

• Step 6: The male pronucleus forms.

• Step 7: Fertilization is complete when the pronuclei merge; upon contact, their membranes breakdown and fuse, allowing the genetic content to intermingle.
  • The result is a single diploid zygote.

Clinical correlations:

Multiple pregnancy is the production of two or more offspring in a single pregnancy.
Entails increased risk of serious complications (including preterm births, placental problems, preeclampsia, and gestational diabetes).

• Though rare in the past, multiple pregnancy has risen dramatically in places where the use of reproductive technologies and maternal age have increased. (For example, as of 2014, 34 twins were born per 1,000 births in the U.S. – CDC)
• Dizygotic (aka, fraternal, non-identical) twins are produced when two oocytes are ovulated and fertilized with two sperm cells; this is the most common type of twinning.
• Monozygotic (aka, identical) twins are produced when a single embryo splits after fertilization.
• Relatedly, polyspermy occurs when one oocyte fuses with two or more sperm; because this creates a zygote with an abnormal number of chromosomes, it is typically lethal.
  • Recall that polyspermy is usually prevented by the cortical reaction of the zona pellucida.

HYPOTHALAMIC-PITUITARY-OVARIAN AXIS

• Regulates oocyte development and release.
• Ovarian follicle produces hormones that prepare the endometrium for implantation in the case of oocyte fertilization.

FOLLICULAR/PROLIFERATIVE PHASE:

GnRH

• Pulsatile release of gonadotrophin-releasing hormone (GnRH) stimulates the anterior lobe of the pituitary gland;
  In response, both LH and FSH are released.

LH

• Stimulates theca interna cells of the ovarian follicle to produce androgens, some of which move into the nearby granulosa cells.

FSH

• Stimulates granulosa cells to increase aromatase activity
  Aromatase converts androgens to estrogens, which exit the granulosa cell.

Estrogen

• Stimulates growth of the endometrium; this characterizes the proliferative phase of the uterine cycle.
• Stimulates growth and activity of granulosa cells, which, in turn, produce more estrogen;
• And, at levels below a set threshold, estrogen inhibits release of FSH and LH from the anterior lobe of the pituitary gland; thus, during the follicular phase of the ovarian cycle, estrogen has negative feedback effects.

OVULATION

• Growing population of granulosa cells raises the plasma estrogen concentration, it eventually surpasses a set threshold and has a positive effect on the anterior lobe of the pituitary gland.
• In response, there is a surge in LH and FSH release (the “pre-ovulatory surge”).
• LH and FSH triggers ovulation, which is the ejection of the secondary oocyte and corona radiate into the peritoneum. Recall that, from here, the oocyte (typically) moves into the uterine tubes.
• Ruptured follicle remains within the ovary.

LUTEAL/SECRETORY PHASE

• Follicular cells are morphologically and physiologically transformed into the corpus luteum, which is now the primary hormone-producing structure

Progesterone

• Stimulates growth and differentiation of the endometrium, thus ushering it to the secretory phase of the uterine cycle.
• Inhibits endocrine activities of the hypothalamus and anterior lobe of the pituitary gland.

Estrogen

• Promotes additional endometrial growth.

Corpus luteum

• The fate of the corpus luteum and endometrium are contingent upon successful fertilization and implantation of the ovulated oocyte.
  If fertilization and implantation occur, the corpus luteum persists and continues to produce the hormones necessary to sustain the endometrium and developing blastocyst until the placenta can take over its endocrine duties.
  If fertilization and/or implantation do not occur, the corpus luteum involutes, aka, regresses, and becomes the corpus albicans (“white body”) which does not produce hormones.

MENSES

• In the absence of progesterone and estrogen, the endometrial tissues begin to desquamate, aka, shed, and are discharged as menstrual blood.
• Menses marks the end of the luteal phase of the ovarian cycle and overlaps with the early events of follicular phase.

Timing:

• Inter and intra-individual variation in cycle length is typical; moreover, some cycles, especially in young women, are anovulatory (an oocyte is not released from the ovary).

Clinical correlation: Dysmenorrhea

• Clinical term for painful abdominopelvic cramping with menstruation
• When over-the-counter drugs aren’t sufficient, dysmenorrhea is often treatable with hormonal contraceptives, which inhibit the cyclic events that produce cramping.

Ovarian follicles:

Functional units of the ovary

• Oocytes
  Female sex cells
  • The ovary houses millions of oocytes. However, only a very small percentage of these will reach maturity; most will undergo atresia (aka, degeneration).
• Follicular cells
  Support the oocyte and produce hormones that regulate ovarian and uterine events (the events of the ovarian and uterine cycles are discussed in detail, elsewhere).

Developmental processes:

Embryologic origins

• Oocytes arise from primordial germ cells (undifferentiated stem cells) that migrate to the gonadal ridge early in fetal development (approximately 3-6 weeks gestation).
• Germ cells proliferate via mitosis.
• Once they reach the gonadal ridge, they become oogonia,which reside in clusters (aka nests).
• The majority of oogonia undergo atresia (aka, degeneration).
• The minority enter meiosis I.

Primordial follicle

• After meiosis I is initiated, the primoridial follicle forms around the oocyte.
• Comprises a single layer of flat granulosa cells, which interact to guide follicular maturation.
• Basement membrane (aka, lamina) surrounds the follicle.
• After the primordial follicle forms, meiosis I arrests in prophase (dictyone phase).

Puberty

• Following puberty, follicles are cyclically “recruited” for further development; at any given time after this, more than 90% of follicles present in the ovary are arrested in the primordial stage.
• Despite meiotic arrest, the oocyte and follicle may continue to grow.

Primary follicle

• Primary oocyte, which has grown larger.
• Zona pellucida is thick a-cellular coat that covers the oocyte; the zona pellucida enables fertilization.
  • It displays sperm receptors and facilitates the acrosome reaction; after fertilization, the zona pellucida prevents additional sperm from joining with the oocyte.
• Granulosa cells proliferate via mitosis and change from flat to cuboidal, which reflects their greater activity.

Secondary follicle

• Primary oocyte achieves meiotic and developmental competence (it is capable of completing meiosis and preparing for implantation).
• Cuboid granulosa cell layers have multiplied from 1 to now 6-9 layers (typically) by the end of the secondary follicular stage.
• Thecal cells, which arise from the ovarian interstitium, begin to accumulate around the basement membrane of the secondary follicle.
• Of the secondary follicles, some will be “recruited” by follicle-stimulating hormone (FSH) to become tertiary follicles.

Early Tertiary Follicle

• Granulosa cells are separated by an antrum, which is a fluid-filled cavity within the follicle; notice that it “pushes” the oocyte to one side of the follicle.
• Thecal cells differentiate into two layers:
  • The theca externa, aka, external thecal cells, form the outermost layer of the tertiary follicle; this layer will form the follicular capsule.
  • The theca interna, aka, internal thecal cells, form the inner layer; these cells will have key roles in hormonal communication and vascularization of the follicle.

Pre-ovulatory surge in LH initiates oocyte development resumption and Meiosis I completion; oocyte enters meiosis II,then arrests in metaphase; a Polar body forms.

Late tertiary stage (aka, Graafian, pre-ovulatory stage):

• Cumulos oophorus is the collection of granulosa cells that support the secondary oocyte and polar body.
• Corona radiata is a subset of the cumulus oophorus that directly surrounds the zona pellucida.

Of the late tertiary follicles, only one, the so-called “dominant follicle,” is ovulated.

Ovulation

• Ovulated secondary oocyte takes the corona radiata with it.
• Ruptured follicle transitions physiologically and morphologically to become the corpus luteum, which acts as a temporary endocrine gland.
• If the oocyte is not fertilized, it will be discharged with the menstrual fluid:
  • In this case, the corpus luteum will involute and become the corpus albicans (“white body”); it will no longer produce hormones.
• If fertilization does occur, the secondary oocyte will resume and complete meiosis II, and a another polar body will be formed.
• If the fertilized oocyte successfully implants, the corpus luteum will persist until the placenta can perform its hormonal duties.

• Spermatogenesis comprises cell division and differentiation processes that produce sperm cells.
• Takes place in the seminiferous tubules of the testes.
• Requires sustentacular cell stimulation from FSH and testosterone (discussed in detail, elsewhere).
• Takes approximately 64 days.

STAGES:

Spermatocytogenesis

• Mitotic divisions create spermatocytes.
• Meiotic divisions create spermatids.

Spermiogensis

• Spermatids differentiate to become sperm (aka, spermatozoa).

Spermination

• Occurs when the sperm disassociate from the sustentacular cell and enter the lumen of the seminiferous tubule.
• From here, sperm cells travel to the epididymis for storage and maturation.

CELL DIVISIONS:

Spermatogonium

• Primordial stem cells from which the sperms originate.
• Undergoes mitosis and creates two cell types:
  • A replication of itself
  • Another that is committed to passing through spermatogenesis = a spermatocyte.

Primary spermatocyte

• Primary spermatocyte undergoes meiosis I to create two daughter cells: secondary spermatocytes

Secondary spermatocytes

• Undergo meiosis II, which produces spermatids.
  This concludes the spermatocytogenesis phase of spermatogenesis.

Spermatids

• Undergo spermiogenesis to form immature sperm; during this time, the cells develop but no longer divide.

Early sperm

• Enveloped in the cytoplasmic processes of the sustentacular cells.
• Have tails, which extend towards the lumen.
• Cytoplasm is concentrated towards one end, the head.
• Are released via spermination into the lumen of the seminiferous tubule.

Maturation:

• Full maturation and motility are not achieved until after ejaculation.
• Uterine tubule fluids within the female reproductive tract triggers capacitation (further maturation), which prepares the sperm for fertilization.

ANATOMY OF A SPERM CELL:

Head

• Comprises the cell nucleus covered by the acrosome; the acrosome contains enzymes that facilitate joining of sperm and ovum at fertilization.

Midpiece

• Comprises mitochondria, which provide the energy for sperm motility.

Tail

• Produces flagellar movements (“back and forth” movements) that enable the sperm to “swim” upon ejaculation.

Clinical Correlation:

• Sperm cells must be able to move through the female reproductive tract for conception to occur; if they cannot, a man may be infertile despite normal sperm count.
• Poor motility may stem from stress, excessive heat, drug effects, and dietary inefficiencies.