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HISTOLOGY OF HUMAN REPRODUCTIVE SYSTEMS I. Introduction

A. Functions of reproductive systems

1. production and transport of gametes 2. production of hormones which control sexual development and which help to

synchronize functions among the organs of the reproductive system 3. protection and nutrition of the embryo during early development (in female eutherial and metatherial mammals)

B. Structure of reproductive systems

1. Gonads (Ovaries and testes)

a. Gonads are exocrine glands which secrete gametes ("eggs", sperm). This can be viewed as holocrine secretion.

b. Gonads contain cells which synthesize and secrete sex steroid hormones in a

typical endocrine fashion. c. Gonads are paired structures in mammals and most, but not all, other vertebrates.

2. Genital ducts and associated glands

a. Male genital ducts (Figure 22.1)

(1) Functions

(a) transport of sperm (b) formation of semen components

(2) Organs

(a) Tubular organs

- Epididymis - Vas deferens - Urethra

(b) Accessory glands (extramural)

- Seminal vesicles - Prostate gland - Bulbourethral gland (Cowper's Gland)

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b. Female genital ducts (Figure 23.1)

(1) Functions

(a) Site of sperm deposition (b) Transportation of gametes (c) Site of fertilization (d) Site of embryo development

(2) Organs (all are tubular)

(a) Oviduct or Fallopian tube (b) Uterus (c) Vagina

3. External genitalia

a. Male (Figure 22.1)

(1) penis (2) scrotum

b. Female

(1) Labia majora (2) Labia minora (3) Clitorus

4. Mammary glands (Figure 23.32) a. functional only in females b. produce milk (complex mixture of lipids and proteins)

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Outline of the human male reproductive tract

Lining Epithelium Tubular Structure Organ Sertoli cells + seminiferous tubules spermatogenic cells simple columnar tubuli recti testis simple cuboidal or rete testis simple columnar pseudostratified columnar efferent ductules (mixed ciliated and absorptive cells) epididymis pseudostratified ductus epididymidis columnar with stereocilia pseudostratified vas (ductus) deferens columnar with stereocilia vas deferens pseudostratified ampulla columnar with stereocilia

seminal vesicle pseudostratified and ejaculatory ducts simple columnar with stereocilia prostate transitional prostatic urethra prostate stratified columnar stratified membranous urethra columnar Cowper's glands stratified penis columnar penile urethra stratified squamous

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II. Microanatomy of the male human reproductive tract

A. Testis (Figure 22.4 - 22.6, 22.13, 22.16, Plate 82, 83)

1. The capsule of the testis contains three layers.

a. Tunica vaginalis = mesothelium (outer layer) b. Tunica albuginea = dense regular collagenous CT c. Tunica vasculosa = thin layer of vascularized loose FECT

2. The human testis has a lobular organization.

a. The human testis is subdivided into approximately 250 lobules by septal extensions from the tunica albuginea.

b. Each lobule contains 1 to 4 seminiferous tubules embedded in a stroma of "loose

FECT" (interstitial connective tissue) which contains blood and lymphatic vessels and macrophages, but lacks typical fibroblasts and other loose FECT cells. The Leydig endocrine cells are located in the interstitial CT.

3. Seminiferous tubules fill most of the volume in the testis.

a. Seminiferous tubules consist of loops (no free ends). b. Seminiferous tubules are composed of a complex epithelium surrounded by

peritubular "connective" tissue (sometimes called lamina propria). c. Two major epithelial cell types occur in seminiferous tubules.

(1) Sertoli cells (sustentacular or supporting cells)

(a) Structure

- form a simple tall columnar epithelium (this arrangement is usually not apparent due to spermatogenic cells)

- have pale staining cytoplasm which is extensively branched and

extends between the spermatogeneic cells - have relatively basally located nuclei which are predominately

euchromatic with prominent nucleoli - attach to one another by zonula occludens

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(b) Function

- form a diffusion barrier (the "blood- testis barrier") between the lumen of the seminiferous tubules and the underlying CT.

- provide nutrients and other materials for sperm differentiation - synthesize and secrete estrogen and an androgen binding protein

(ABP, which binds testosterone)

(2) Spermatogenic cells

(a) Structure

- Spermatogenic cells are spherical until the later stages of sperm differentiation, then become very elongated cells.

- Spermatogenic cells have pale cytoplasm and nuclei which are initially

a mixture of heterochromatin and euchromatin and become heavily heterchromatic during sperm differentiation.

- Interconnected clusters of spermatogenic cells are enfolded by Sertoli

cells. - The spermatogonia which divide to produce the clusters of

spermatogenic cells are enfolded by the basal region of the Sertoli cells.

- Three clusters of spermatogenic cells (each at a different stage in

spermatogenesis) are typically observed in a given location at one time.

- The most mature clusters are located closest to the lumen of the

seminiferous tubule.

(b) Function

- Spermatogonia produce cells which undergo meiosis and then differentiate into sperm.

d. Peritubular "connective" tissue (tunica propria or "lamina propria") surrounds

each seminiferous tubule.

(1) A thin basal lamina surrounds the epithelial components of each seminiferous tubule.

(2) 3 to 5 layers of myoid cells (smooth muscle-like cells) surround the basal

lamina. (3) The myoid cells are interspersed with fine collagen fibers.

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4. Interstitial connective tissue (stromal connective tissue) occurs between seminiferous

tubules in the testis.

a. Testicular interstitial tissue resembles highly vascular loose FECT with fine collagen fibers and macrophages, but few or no typical fibroblasts occur.

b. Interstitial cells of Leydig (Leydig cells) are distributed singly or in small clusters in

interstitial stromal tissue.

(1) Structure

(a) Leydig cells are large cells with pale vacuolated cytoplasm containing extensive sER and occasional crystals of Reinke (refractile crystals of unknown function).

(b) Leydig cells have spherical nuclei with both euchromatin and

heterochromatin and distinct nucleoli.

(2) Function

Synthesize and secrete testosterone and related androgens

5. Tubuli recti (Figure 22.19) receive sperm from the seminiferous tubules.

a. Tubuli recti connect the ends of the seminiferous tubules to the rete testis. b. Tubuli recti are lined by simple columnar epithelium which drops to simple cuboidal

just before the rete testis.

6. The rete testis lies "downstream" of the tubuli recti.

a. The rete testis connects the tubuli recti to the efferent ductules. b. The tubules in the rete testis are lined by simple cuboidal or columnar epithelium

(each cell has a single apical cilium) embedded in highly vascular loose FECT. c. The rete testis consists of an interconnected network of tubules.

7. Efferent ductules (ductuli efferentes, Figure 22.21) occur where the testis and epididymis interconnect.

a. The efferent ductules connect the rete testis to the ductus epididymidis. b. The efferent ductules are lined by columnar epithelium which is pseudostratified

(due to a sparse population of basal cells) over most of the length of the ductules. Lining cells may be ciliated (taller cells) or have microvilli (shorter cells). A thin layer of circular smooth muscle occurs on the distal parts of the ductules.

c. Ciliated cells move sperm along ducts. Cells with microvilli transport fluid from the

lumen of the ductule into the surrounding connective tissue and take up particles by endocytosis.

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B. Genital ducts (tubular organs)

1. Epididymis (Figure 22.22, 21.23, Plate 84)

a. Gross anatomy

The epididymis is traditionally divided into three anatomical regions.

(1) The initial segment (caput epididymis or head region) contains the efferent ductules emerging from the testis and the initial part of the ductus epididymis.

(2) The middle segment (corpus epididymis or body region) runs along the side of

the testis and contains most of the length of the ductus epididymis. (3) The terminal segment (cauda epididymis or tail region) contains the terminal

segment of the ductus epididymis which connects with the vas deferens.

b. Microanatomy

(1) Capsule = dense regular collagenous CT (2) Stroma = loose FECT (3) Parenchyma = the ductus epididymis = a long highly convoluted tube

composed of epithelial and muscular tissue

(a) The epithelial lining is simple columnar epithelium in the initial part of the efferent ductules and changes to pseudostratified columnar epithelium with stereocilia in the ductus epididymis.

(b) A thin smooth muscle layer surrounds the epithelium. The muscle is

mainly circular along most of the ductus epididymis, but near the vas deferens the muscular layer becomes thicker and longitudinally arranged smooth muscle cells are present inside and outside of the circular layer.

(4) The functions of the epididymis are not fully understood. The epithelium is

clearly involved in absorption, and up to 99% of the fluid volume leaving the seminiferous tubules may be resorbed before the fluid leaves the epididymis. In many mammals, sperm collected from the caput epididymis will not fertilize eggs, but sperm collected from the caudate epididymis will. At least in those species, the epididymis is essential in sperm functional maturation and may function by adding glycoproteins and other molecules secreted by epididymal cells to the glycocalyx of the sperm. In addition sperm may remain in the terminal segment for up to several weeks, allowing "storage" in a protected environment.

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2. Vas deferens (also ampulla and ejaculatory ducts)(Figure 22.25, Plate 85)

a. Mucosa

(1) Epithelium = pseudostratified columnar epithelium with stereocilia (2) Lamina propria = loose to moderately dense FECT

b. Muscularis externa

Inner longitudinal smooth muscle layer Middle circular smooth muscle layer (thickest) Outer longitudinal smooth muscle layer The muscle layers are lost in the ejaculatory ducts.

c. Adventitia

Loose to moderately dense FECT

3. Urethra

Three regions may be distinguished.

(1) Prostatic urethra

(a) The prostatic urethra is located within the prostate gland. (b) The prostatic urethra is connected to the bladder and to the vasa deferens. (c) The luminal epithelium within the prostatic urethra makes a gradual transition

from transitional epithelium to pseudostratified or stratified columnar epithelium.

(2) Membranous urethra (short)

The membranous urethra is a short segment lined by stratified columnar epithelium which occurs between the prostate and the penis.

(3) Penile urethra (Figure 22.32)

(a) The penile urethra is located within the corpus spongosum of the penis. (b) The lining epithelium of the penile urethra makes a gradual transition from

stratified columnar to stratified squamous.

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C. Accessory (extramural) Glands

1. Prostate gland (Figure 22.27, 22.29, Plate 86)

a. The prostate is a compound tubulo-alveolar gland which surrounds the urethra just below the urinary bladder. The prostate contains three "levels" of secretory units lined by simple columnar to pseudostratified columnar epithelium. The cells have basally located round nuclei and moderately acidophilic apical cytoplasm containing numerous secretory granules. Secretion appears to occur by merocrine and apocrine mechanisms. Prostatic concretions (corpora amylacea) occur in some alveolar lumens and may be large (up to 1 mm) with concentric layers and may become calcified with age.

b. Glandular organization may be described in terms of layers of the urethra wall, with

prostatic secretory units located in three levels and connected to the lumen by 15 to 25 independent ducts.

(1) Mucosal glands are located in the mucosa layer of the urethra and empty

individually into the superior surface of the urethra. The mucosal glands are usually responsible for benign hyperplasia of the prostate.

(2) Submucosal glands are located in the submucosa of the urethra and empty

into ducts which empty into the lateral margins of the urethra. (3) Main prostatic glands are external to the submucosa and empty into large

duct systems which join the urethra inferiorly and medially to the ducts of the submucosal glands. The main glands are the most frequent sites of malignant prostate cancers.

c. Prostatic stroma = loose to moderately dense FECT (called dense in the text)

containing abundant smooth muscle, highly vascular d. Capsule = Moderately dense to dense fibroelastic connective tissue containing

smooth muscle, extends into the gland to form septa e. The secretory product contains citric acid, acid phosphatase, and proteolytic

enzymes.

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2. Seminal vesicles (Figure 22.26, Plate 87)

a. The seminal vesicles are tubular structures which are heavily folded and are therefore usually described using tubular organ terminology.

(1) Mucosa (highly folded)

(a) The epithelium is pseudostratified cuboidal/low columnar epithelium. Some cells may have stereocilia, and most cells contain large acidophilic apical secretory granules.

(b) The lamina propria is highly cellular loose FECT, rich in elastic fibers, and

contains some smooth muscle cells.

(2) Muscularis externa

Inner circular layer of smooth muscle Outer longitudinal layer of smooth muscle

(3) Adventitia

loose to moderately dense FECT, rich in elastic fibers

b. Secretory product is viscous, alkaline, and high in fructose.

3. Bulbourethral (or Cowper's) glands (Figure 22.30)

a. Parenchyma tissue

(1) Compound tubulo-alveolar glandular units lined by cuboidal to low columnar mucous epithelium

(2) Collecting ducts - simple columnar epithelium (3) Excretory ducts - pseudostratified columnar epithelium which may become

stratified columnar in the main duct connecting each gland to the urethra

b. Stroma and "capsule" are loose to moderately dense FECT containing elastic fibers, smooth muscle, and skeletal muscle because these glands are embedded in the perimeter of the sphincter urethrae muscle

c. Secretory product is mucous-like and rich in sialoproteins and amino sugars.

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D. External Genitalia

Penis (Figure 22.31, 22.32)

1. The penis is a tubular organ consisting of the penile urethra, surrounding connective tissue, and an outer covering of skin.

2. Penile urethra - as previously described 3. Connective tissue and muscular components

a. Cavernous or erectile tissue is highly vascularized.

(1) Corpora cavernosa (singular = corpus cavernosum) are paired and dorsally (superiorly) located.

(2) The corpus spongiosum or corpus cavernosum urethrae surrounds the penile

urethra.

b. The tunica albuginea is a layer of dense regular collagenous CT which surrounds the corpora cavernosa.

c. Less dense FECT and a thin layer of smooth muscle surround the corpus

spongiosum and is also called a tunica albuginea. d. Loose FECT fills the spaces between the denser connective tissue layers and the

overlying skin.

4. The outer covering of the penis is thin skin.

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III. Microanatomy of the female human reproductive system

A. Ovary (Figure 23.2 - 23.8, 23.11, 23.13, Plate 88, 89, 90)

1. Overall structure

a. The outer serosa consists of the germinal epithelium underlain by the tunica albuginea.

The germinal epithelium is a simple cuboidal/columnar epithelium which is actually a form of mesothelium. The tunica albuginea is a thin layer of dense regular collagenous CT.

b. The cortex lies between the serosa and the medulla.

(1) The parenchyma of the cortex includes ovarian follicles, related structures (e.g., corpora lutea), and interstitial cells. Follicles and related structures will be described below.

Interstitial cells are rounded steroid secretory cells which occur (frequently in clumps) in stromal CT. Interstitial cells are thought to originate from theca interna cells of atretic follicles. Interstitial cells are rare in actively cycling human ovaries but are present prior to puberty and also accumulate during pregnancy. Large accumulations of interstitial cells are normal in ovaries of mammals which have large litters and are called the interstitial gland.

(2) The stroma of the ovarian cortex is called stromal connective tissue. Stromal

CT contains tightly packed spindle-shaped cells separated by fine collagen fibers. White blood cells may occur in stromal CT at some parts of the menstral cycle.

c. The medulla of the ovary contains loose FECT with numerous blood vessels and

some stromal CT.

Hilus cells occur in the medulla at the hilus (attachment of the ovary to the mesovarium) and in the adjacent part of the mesovarium (ovarian mesentery). Hilus cells resemble the Leydig cells of the testis and appear to secrete androgens.

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2. Ovarian follicles and related structures

a. Cell types

(1) Oocyte (normally one per follicle)

(a) Large cell (about 5-10x the diameter of most body cells) (b) granular cytoplasm (c) large euchromatic nucleus (d) prominent nucleolus

(2) Follicle cells

(a) Much smaller than oocytes (b) Shape and number varies according to stage of follicle development

[1] Granulosa cells

- Granulosa cells form an epithelium around the oocyte. - Granulosa cells provide nutrients and other materials to the

developing oocyte. - Granulosa cells secrete progesterone.

[2] Theca cells

- Theca are apparently derived from stromal connective tissue cells which assemble around a follicle as it develops.

- Theca interna cells are rounded cells with weakly acidophilic

cytoplasm and secrete estrogen. - Theca externa cells are spindle-shaped cells with smooth muscle

properties.

b. Developmental sequence of follicle types

(1) Primordial follicle

(a) A primordial follicle consists of an oocyte surrounded by a few simple squamous epithelial cells.

(b) Promordial follicles occur in clusters ("egg" nests) in the outer cortex.

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(2) Primary follicle

(a) A primary follicle consists of an oocyte surrounded by a simple cuboidal/columnar epithelium.

(b) During the primary follicle stage, the zona pellucida (acellular layer) begins

to develop between the oocyte and the follicle cells.

(3) Stratified follicle (called a primary follicle by most histology texts, called a secondary follicle by some developmental biologists)

(a) A stratified follicle consists of an oocyte surrounded by stratified cuboidal

epithelium (these cells are referred to as granulosa cells). (b) Stromal cells condense around the follicle to form the theca folliculi (the

cells are referred to as thecal cells). (c) A basement membrane develops between the granulosa and thecal cells. (d) The zona pellucida becomes much thicker.

(4) Antral follicle (called a secondary follicle by most histology texts, called a tertiary follicle by some developmental biologists)

(a) A follicular cavity (antrum) develops within the granulosa cell layers. (b) Granulosa cells are identified according to their position within the follicle:

the cumulus oophorous cells are around the oocyte and the stratum granulosum cells are around the follicular cavity.

(c) Differentiation of the thecal cells into the theca interna (oval cells) and

theca externa (spindle-shaped) cells is visible. (d) The largest antral follicles are referred to as Graafian follicles (or mature

follicles). These follicles are ready for ovulation.

c. Ovulation

During follicle maturation, expansion of the volume of the follicle occurs primarily toward the surface of the ovary. As a result, mature Graafian follicles protrude from the surface of the ovary. During the ovulation process the stratum granulosum, the theca interna, the theca externa, the tunica albuginea, and the germinal epithelium all rupture. The oocyte with its surrounding zona pellucida and cumulus oophorus cells is expelled along with most of the antral fluid. The stratum granulosum, the theca interna, and the theca externa are all retained in the ovary.

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d. Corpus luteum formation

Following ovulation, the ruptured Graafian follicle is slowly transformed into a corpus luteum which becomes highly vascularized.

(1) Granulosa cells are transformed into granulosa lutein cells which have the

appearance of typical steroid secreting endocrine cells with pale smooth cytoplasm. These cells secrete progesterone.

(2) Thecal cells, especially theca interna, become transformed into theca lutein

cells. These cells also become typical steroid secreting endocrine cell and produce estrogen. Theca lutein cells are usually a little smaller and darker staining than granulosa lutein cells.

B. Genital ducts

1. Oviducts or Fallopian Tubes (Figure 23.16, Plate 91)

a. Oviducts are made up of three anatomical regions.

(1) Ampulla or infundibulum = the enlarged open end of the oviduct (2) Isthmus = the middle part of the oviduct (3) Intrauterine or intramural portion = the part of the oviducts embedded in the

wall of the uterus

b. The Mucosa forms folds or plicae, especially in the ampulla.

The epithelium is a simple columnar epithelium containing a mixture of ciliated cells and non- ciliated secretory cells. The lamina propria is highly cellular CT which is similar to stromal CT in the ovary and uterus.

c. The muscularis externa contains bundles of smooth muscle. The inner circular layer is thicker than the outer longitudinal layer.

d. The serosa contains loose FECT and is surrounded by a mesothelium over most of

the oviduct, but is reduced to an adventitia in the intrauterine part of the oviduct.

2. Body of the uterus (Figure 23.17 - 23.19, Plate 92, 93)

a. Terminology

(1) Mucosa = endometrium (2) Muscularis externa = myometrium (3) Serosa = perimetrium

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b. The endometrium consists of an epithelium and a lamina propria.

(1) The epithelium is a simple columnar or pseudostratified columnar epithelium. (2) The lamina propria is stromal connective tissue related to the stromal CT in

the ovary. Uterine stromal CT contains stellate cells with euchromatic nuclei. Spaces around the cells contain reticular fibers and proteoglycans. Macrophages, granulocytes, lymphocytes, and plasma cells occur in moderate numbers at various points in the menstral cycle.

(3) The lamina propria contains numerous simple tubular glands and is highly

vascularized. (4) The endometrium (both epithelium and lamina propria) undergoes extensive

cyclical changes in response to changing estrogen and progesterone levels during the menstral cycle or during pregnancy. The endometrial responses during a typical menstral cycle can be described as three phases.

(a) The proliferative or growth phase in the endometrium occurs in response

to estrogen secretion during follicle growth in the ovary. The endometrium thickens and the epithelium of the glands in the base of the endometrium proliferates and spreads to cover the connective tissue exposed by menstration.

(b) The endometrium shifts into the secretory phase in response to the

mixture of estrogen and progesterone secreted by the corpus luteum. During this phase, the endometrium continues to thicken and the glands begin the actively secrete.

(c) The menstral phase occurs in response to the drop in steroid production

when the corpus luteum regresses. The spiral arteries at the base of the endometrium rupture and flood the stromal CT with blood. The endometrium above this level degenerates and is shed.

c. The myometrium contains smooth muscle arranged in bundles. Although the

layering is indistinct, an inner longitudinal layer, a middle circular or spiral layer (thickest layer, highly vascular), and an outer longitudinal layer have been described.

d. The perimetrium on exposed surfaces is a serosa consisting of thin loose FECT

and a mesothelium.

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3. Cervix of the uterus (Figure 23.22 - 23.24, Plate 94)

a. The mucosa consists of an epithelium and a lamina propria.

(1) The epithelium in the endocervix (inside the canal in the cervix) is a simple tall columnar epithelium containing a mixture of ciliated and mucous secretory cells.

(2) The epithelium in the exocervix (cervix survace exposed in the vagina) is

stratified squamous epithelium. (3) The transition point between these two epithelia is the point of origin of many

cervical cancers. Expansion of the simple epithelium onto the exocervix causes the red area referred to as cervical "erosion".

(4) The lamina propria is loose to moderately dense FECT. (5) The mucosa of the endocervix is heavily folded to form irregularly shaped

branched tubular glands called cervical glands. These glands are the major source of cervical mucus.

b. The "muscularis" contains collagenous CT and bundled smooth muscle

surrounded by the body wall tissues.

4. Vagina (Figure 23.28, 23.29, Plate 97)

a. The mucosa of the vagina consists of epithelium and connective tissue.

(1) The epithelium is nonkeratinized or slightly keratinized stratified squamous epithelium.

(2) The "lamina propria" (actually includes submucosa) consists of a layer of

highly vascular loose FECT (containing numerous lymphocytes) next to the epithelium, a middle thick layer of moderately dense FECT, and a thin deep layer of loose FECT next to the muscularis.

b. The muscularis externa consists of a thin inner circular smooth muscle layer and a

thicker outer longitudinal smooth muscle layer. A sphincter of circular skeletal muscle surrounds the inferior (outer) end of the vagina.

c. The adventitia consists of dense heavily elastic FECT next to the muscularis and

loose FECT more externally.

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C. Mammary Glands (Figure 23.32 - 23.36, Plate 98, 99)

1. "Resting" stage (post-puberty, pre-pregnancy)

a. The gland consists of scattered "islands", each containing a few branched simple cuboidal/low columnar (with scattered basal myoepithelial cells) lined tubular elements (considered to be duct tissue) with occasional alveoli. Each "island" is embedded in loose FECT to form a lobule

b. The lobules are separated by moderately dense to dense irregular FECT containing

scattered adipose cells. The dense CT is continuous with the fascia in the deep hypodermis of the thorax wall.

2. Proliferative stage (during pregnancy)

a. Each lobule enlarges by forming numerous additional tubular "duct" structures and then (during late proliferation) by forming enlarged alveoli at the ends of the tubules. The tubules and alveoli may contain small aggregates of secretion, but large aggregates of secretion and large alveoli (more than 2-3x the tubule diameter) are not present.

b. The loose FECT around each lobule expands with the epithelial components of the

lobule. Visible numbers of lymphocytes begin to appear in the loose FECT. c. The dense FECT septae appear thinner relative to the lobules. This is partially due

to compression of the septae by the enlarging lobules and partly because the lobules themselves are larger.

d. The gland goes from appearing to be mostly dense FECT to appearing to be mostly

duct epithelium.

3. Secretory stage (during lactation)

a. Each lobule now appears to consist primarily of enlarged alveoli which usually appear to have a low simple cuboidal lining. Acidophilic secretion fills each alveolus. Duct lining tissue (taller cuboidal epithelium) is not easily visible except in interlobular ducts.

b. The loose FECT within each lobule is only visible by looking closely between the

alveoli. No region of loose FECT is visible around each alveolus. c. The dense FECT septae are now very narrow bands of tissue around each of the

lobules. d. Most of the gland is now composed of alveolar epithelium with only very small areas

of connective tissue.