Male and Female Reproduction

Male Reproductive Physiology and Spermatogenesis

Goals of Spermatogenesis

Spermatogenesis = proliferation + meiosis + differentiation

• Provide the male with continuous supply of gametes via stem cell renewal

• Provide genetic diversity

• Provide an immunologically privileged site where germ cells are safe from the males immune system

Male Reproductive Physiology

• Endocrine control of testicular function

• Testicular structure and function

• Spermatogenesis

Production of Male Gametes

• Spermatogonia produced after fetal gonadal differentiation are quiescent until puberty

• At puberty, maturation of the hypothalamus begins the endocrine control of gamete production in both males and females

Control of Spermatogenesis Requires the Hypothalamic-Pituitary-Gonadal (HPG) Axis

• Hypothalamic Gonadotropin Releasing Hormone (GnRH) binds GPCR on gonadotropes in Anterior Pituitary

• Activates Gq to initiate PLC/Calcium cascade (see TRH signaling Thyrotropes)

• Gonadotropes synthesize Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) and release via exocytosis

• FSH and LH act on specific targets in the testes

  • FSH activates Sertoli cells

  • LH activates Leydig cells

GnRH

Only tonic release of GnRH in males

GnRH, LH, FSH

LH, T

Interrelationship of Hormones and Testis

LH and FSH receptors are GPCR and activate via Gs to stimulate cAMP production

Interrelationship of Hormones and Testis 2

Interrelationship of Hormones and Testis 3

Interrelationship of Hormones and Testis 4

“Free” testosterone is controlled by:

• Steroid Hormone Binding Globulin (SHBG; from the liver) in the blood

• Androgen Binding Protein (ABP: from Sertoli cells) in the testis

• Same gene, different cells producing the protein and thus different post-translational modifications

Endocrine Control of Spermatogenesis

Male Reproductive System is a Manufacturing, Processing, Storage and Delivery Mechanism

Environmental Regulation is Critical for Sperm Production

Thermoregulation:

• Cremaster and tunica dartos muscles

• Pampiniform plexus

Environmental Regulation is Critical for Sperm Production 2

Thermoregulation

Environmental Regulation is Critical for Sperm Production 3

Thermoregulation via the Pampiniform Plexus

Location, location, location…

Sperm stored in the caudal epididymis are much cooler than normal body temperature

Environmental Regulation is Critical for Sperm Production 4

Spermatogenesis thermoregulation requires understanding of neuronal and respiratory physiology

Extended Elevated Temperature Can Lead to Infertility

• Thermoregulation is critical to proper function and storage of sperm

• Prolonged elevated scrotal temperature decreases:

  • Sperm production rates

  • Sperm quality

  • Fertility

• Some causes include:

  • Hot tubs, tight clothes, laptop computers, etc…

Structure of Testis is Critical to Function

All the seminiferous tubules from an adult man placed end to end would span an average length of approximately 500 to 600 meters!

Structures are Important for Sperm Production and Transport

Structures are Important for Sperm Production and Transport 2

Structure of Testis is Critical to Function 2

Tight junctions between the Sertoli cells provide the blood testis barrier, not the basement membrane

Spermatogenesis

• Three Phases of Spermatogenesis

  • Proliferation

    • Stem cell renewal

  • Meiosis

    • Genetically diverse haploid cells

  • Differentiation (spermiogenesis)

    • Transformation into DNA delivery device (non-functional)

Basement membrane

Proliferation Phase of Spermatogenesis

• Stem cell renewal

  • Without self renewal of the spermatogonia stem cells, then there could be no continuous supply of sperm throughout the male’s life

• Proliferation spermatogonia are diploid

Proliferation Phase of Spermatogenesis

• Mitotic division of spermatogonia

  • Number of mitotic divisions depends on species

Meiotic Phase of Spermatogenesis

• Moves to the immunologically “safe” side of the Sertoli cell tight junctions

• Involves the primary and secondary spermatocytes

• Insures genetic diversity

  • Homologous recombination (crossing over)

• Two meiotic division with equal distribution of cytoplasm produces haploid (1N) spermatids

Spermatogenesis Flow Chart

Spermatogenesis Flow Chart 2

Differentiation Phase

• Spermiogenesis

• Morphological transformation of the spermatids to spermatozoa

  • Phases

    • Golgi

    • Cap

    • Acrosomal

    • Maturation

Duration of Spermatogenesis in Livestock and Humans

Sperm Production Estimates

Consider the physiological and/or evolutionary reasons for diverse sperm

Sperm Transport & Maturation

• Spermiation to Ejaculation

  • Letting go and escape

Epididymal Transport Changes the Spermatozoa

• Epididymal Transport Time

Critical components to sperm motility and viability are acquired during epididymal transport

Emission & Ejaculation

• Emission

  • Discharge of accessory gland secretions and sperm into urethra

    • Specific substances are produced in each of the accessory glands and contribute differently depending on species

• Ejaculation

  • Expulsion of semen from urethra

Semen Contains Seminal Plasma and Spermatozoa

• Seminal Plasma is the fluid “delivery system” for spermatozoa

  • Seminal plasma carries the spermatozoa out of the body

• Not an absolute requirement for fertility

• Produced by

  • Epididymis

  • Ampulla

  • Seminal vesicles (vesicular glands)

  • Prostate gland

  • Bulbourethral glands (Cowper’s glands)

Seminal Plasma Helps Protect and Prepare Spermatozoa

• Coats sperm surface proteins and carbohydrates

  • Stimulates capacitation

  • Prevents over capacitation leading to premature acrosome reaction

• Energy substrates

• pH buffer

• Immune system modulation

• Induction of ovulation (in some camelids)

Spermatogenesis is Complex and Failure is Common

• Perturbations to the DNA during any phase of spermatogenesis (but especially meiosis) can lead to abnormalities that would be passed on to offspring

• Insults to spermatogenesis (like heat or toxins) can lead to defective, low quality spermatozoa incapable of proper fertilization or subsequent failure in embryonic development

• Failure of spermatogonia self-renewal would lead to a depletion of sperm production and infertility

Female Reproductive Physiology and Oogenesis

Oogenesis and follicle development

Primordial follicles form during early fetal development

Primordial Germ Cells Differentiate to Oogonia in the Ovary

• Oogonia proliferate via mitosis

• Enter first phase of meiosis and then become quiescent (meiotic arrest)

Oogonia to Oocytes

• Oogonia are the mitotic stem cells that lead to the meiotic oocytes

• In mammals a female is born with a fixed number of oocytes within the ovaries, which over the years progressively decreases without possibility for renewal

• Once the oocyte reserve has been exhausted, ovarian senescence occurs

  • Referred to as the menopause in women

• The fertilize lifespan of a female depends on

  • the size of the oocyte pool at birth

  • the rapidity of the oocyte pool depletion

  • These are heritable traits!

Lifestyle Germ Cell/Oocyte Chart in Women

Primordial Follicle and Oocyte Meiotic Arrest

• Oogonia enter meiosis and is surrounded by epithelial cells

  • Germ cell is now called an oocyte

  • Epithelial cells are now granulosa cells

• The first meiotic arrest occurs during prenatal life when the oocyte proceeds through the first stages of meiosis and stops at the diplotene stage of prophase I in the first meiotic division

• The oocyte remains in meiotic arrest for many years until the meiotic process is resumed by the preovulatory surge of LH, removal from the follicle, or follicle death by atresia

The primordial follicles present at birth represent the POOL of follicles that will be available throughout the female’s life

Activation of Oocyte Growth

Activation of a subset of genes in the oocyte induces a few primordial follicles a day to leave the pool and begin to grow. The rest of the primordial follicles stay in the pool (non-growing)

Development of Primordial Follicles to Primary Follicles

Signaling interactions (+ve, stimulatory; -ve inhibitory) involved in the primordial-to-primary follicle transition; kit ligand (KL) and basic fibroblast growth factor (bFGF) secreted by pre-granulosa cells and oocyte respectively, have stimulatory effects on oocytes and granulosa cells; they also promote recruitment of theca cells from the surrounding stromal/intestinal cell population

Once Out of the Primordial Pool, Oocytes Have Only Two Outcomes: Live or Die…

Summary

• Males and females use many of the same hormones to accomplish different physiological processes

• Age of puberty is controlled by many factors, but genetics and nutrition play major roles

• Thermoregulation of spermatogenesis and sperm storage is critical to fertility

• HPG axis maintains endocrine control of spermatogenesis

• High local concentrations of testosterone are required for proper spermatogenesis

• Spermatogenesis is divided into phases: Proliferation, meiosis and differentiation

• Spermiogenesis is the morphological change of a spermatid into a fully formed by not yet functional spermatozoa

• Oogonia divide mitotically during fetal development, then enter meiosis and arrest

• The pool of primordial follicles is fixed during fetal development and does not renew

• The oocyte controls the growth of the follicle and thus its own growth, once the oocyte initiates growth, it must continue to ovulation or atresia