HPG Axis & Steroid Hormones

Hypothalamic-Pituitary-Gonadal (HPG) Axis

• GnRH, gonadotropin-releasing hormone, is produced in the hypothalamus.
• LH stands for luteinizing hormone.
• FSH stands for follicle-stimulating hormone.
• Somatic cell types depend on whether the gonad is male or female.
• Somatic cells support gametogenesis directly or through steroids.
• Actions outside gonads are supported by steroid cell types

Steroidogenic Pathway

• Adione = androstenedione.
• DHEA = dehydroepiandrosterone.
• DHT = dihydrotestosterone.

Feedback Regulation

• The main hormone product of the testes is testosterone (an androgen)
• Testosterone converts to DHT within target cells.
• The main hormone product of the ovaries is estradiol (an estrogen) and progesterone (a progestin).
• All gonadal steroids mediate negative feedback at the hypothalamus and anterior pituitary, except estradiol under certain conditions.
• Sustained high levels of estradiol will trigger surge release of LH/FSH which is positive feedback.

Human Male Reproductive System

• Testicular migration into the scrotal sac is a feature of some species of mammals; this requires testosterone.
• Normal spermatogenesis requires a temperature 2-3° less than body temperature in some species.
• Failure of the testes to descend results in cryptorchidism.
• The testes contain seminiferous tubules where sperm develop, and the epididymis and vas deferens for sperm storage and transport.
• In spermatogenesis, spermatogonia undergo mitotic division, primary spermatocytes enter meiosis I, secondary spermatocytes initiate meiosis II, and spermatids complete meiosis.

Spermatozoan Structure

• The head of a spermatozoan encapsulates the acrosome which contains enzymes to aid fertilization, and also contains the nucleus.
• The mid-piece contains mitochondrial spirals.
• The tail contains microtubules for propulsion, which is also known as the flagellum.

Endocrine Control of Spermatogenesis

• GnRH influences the anterior pituitary to release FSH and LH.
• FSH and LH stimulate the production of testosterone in Leydig cells.
• Sertoli cells produce products needed in spermatogenesis.

Testicular Androgens

• Testicular androgens have a negative feedback control on LH/FSH and GnRH.
• The primary sex characteristics supported by testicular androgens are the development and maintenance of internal and external genitalia, and spermatogenesis.
• Secondary sexual characteristics promoted by testicular androgens are protein synthesis and muscle growth.
• The main secreted steroid is testosterone, which is converted to DHT in target cells, which has a higher affinity for the androgen receptor.
• DHT, versus testosterone, is required for differentiation of external genitalia during development, also development and support of accessory sex glands.
• Related traits that DHT also plays a role in are male pattern baldness, acne, and facial hair.

Human Female Reproductive System

• The ovaries connect to the uterus via the fallopian tubes.
• The endometrium is the inner lining of the uterus, with the myometrium smooth muscle of the uterus.

Ovarian Structures

• Oocytes are located within follicles, starting as a primordial follicle, maturing into primary, secondary, and tertiary follicles,.
• During ovulation, the oocyte is released from a ruptured follicle.
• After the egg is released, the corpus luteum and regressing corpus luteum remain.

Follicular Phase

• The follicular phase begins with luteal regression, low ovarian steroids, which causes menses.
• In the ovary, a selected follicle begins to grow and secretes estrogen.
• Sustained exposure to high estrogen, when progesterone is low, causes a massive release of gonadotropins, the "LH surge," which results in ovulation.
• Part of endometrial lining sheds during steroid withdrawal, causes menses in the uterus.
• Rising estrogen from a maturing follicle stimulates regrowth of the lining in the "proliferative phase."

Luteal Phase

• The luteal phase begins with the LH surge, which triggers ovulation.
• The oocyte escapes the ovary, completes meiosis I in response to the LH surge, then arrests in meiosis II.
• Somatic cells of the ovulatory follicle transform into luteal cells forming a solid, progesterone-secreting structure called "luteinization".
• High ovarian steroids suppress gonadotropins, preventing the growth of large follicles.
• In the absence of pregnancy, luteal regression occurs after ~12 days.
• Under the influence of progesterone and estrogen, the uterus is prepared for pregnancy resulting in the "secretory phase".
• Luteal regression causes steroid withdrawal, leading to menses.

Genetic Sex Determination in Fetal Development

• Chromosomal sex is determined at fertilization
• Female parent is XX
• Male Parent is XY
• Female offspring inherit XX
• Male offspring inherits XY
• Urinary and reproductive systems are inter-related during sex determination

Embryonic Development

• In early development, there are indifferent gonads.
• Males retain the mesonephric duct, while females retain the paramesonephric duct.
• There are three sets of kidneys, the first two sets degenerate.
• Each sex forms para mesonephric ducts, but only in females.
• Males use ductwork left from the primitive kidney, called the mesonephric duct.
• Females use parallel ductwork, called the paramesonephric duct.

Development of Internal Genitalia

• In males, Wolffian structures persist, while Mullerian ducts degenerate.
• In females, Mullerian ducts persist, and Wolffian ducts degenerate.
• Wolffian derivatives include the epididymis, vas deferens and accessory sex glands such as the prostate.
• Mullerian derivatives include the fallopian tubes, uterus, cervix and upper vagina.

Sexual Differentiation

• Sry is the master transcription factor expressed by pre-Sertoli cells.
• Sertoli cells secrete anti-Müllerian hormone (AMH).
• Testosterone from Leydig cells acts on the mesonephric (Wolffian) duct and develops the male tract.

Signalling Involved in Reproductive Development

• To build a 'bipotential' gonad: germ cell precursors arrive and somatic cells organize around them.
• Somatic cells in testes express Sry.
• In the presence of no Sry an ovary will form.
• Presence of Sry cells yields a testis.
• Sertoli cells release AMH
• Female external genitalia has a retained Mullerian duct

Disorders of Sexual Differentiation

• Consequences of mutations for XY individuals with a loss of function in 5α-reductase, or mutations that cause a loss of function in the androgen receptor may cause disorders of sexual differentiation.

Fertilization-Parturition

• The inner cell mass and trophectoderm are the first differentiated cell types in mammalian embryos.
• The placental membrane is derived from the trophectoderm, and the embryo proper is derived from the inner cell mass.

Parturition

• Parturition involves cervical softening ('ripening'), initiation of rhythmic uterine contractions, delivery of the baby, and expulsion of the placenta.
• Parturition is controlled by a sequential cascade of hormones; however, the exact hormones and cascade vary among species of mammals.
• A consistent finding is positive feedback/neuroendocrine reflex involving oxytocin.