LO1:The HPG axis
how is female and male gametogenesis different? describe the phases of the menstrual cycle...
*In males* gametogenesis is continuous, meaning that there is a constant production of sperm. *In females*, gametogenesis is cyclic and only one oocyte is produced per month. There are three phases to the menstrual cycle, but it normally lasts 26-32 days (with differences between women arising in the follicular phase) 1. Follicular/Proliferative phase is generally 14-20 days. This starts at day 1, the first day of menses 2. Ovulation takes place at the end of the follicular phase, typically at day 14. Levels of LH and FSH peak here, and levels of oestrogen begin to fall 3. Luteal/ Secretory phase is always 14 days. Levels of progesterone rise throughout this phase
describe the role FSH, LH and hCG what are they secreted by, what do they act on? what is their structure?
*LH* secreted by Gonadotrophins act on:leydig cells of the testes, theca and granulosa cells of the ovaries.(oocyte release) structure:common alpha unique beta chain, on ecarbohydrate chain receptor:LHCGR *FSH* secreted by gonadotrophins, acts on the sertoli cells of the testes, granulosa cells of the ovaries (oocyte maturation) structure:common alpha and unique beta chain, two carbohydrate chains receptor: FSHR *hCG* syncitiotrophoblast clles Acts on: luteal cells of the ovary structure:common alpha chain unique beta chain and two carbohydrate chains receptor:LHCGR
Describe the role of the hypothalamus... what does it release? which of these hormones controls the HPG axis? when is GnRH released?
*The hypothalamus is a collection of nuclei between the midbrain and forebrain that controls endocrine function via the pituitary gland* -the initial hormone that controls the HPG axis is gonadotrophin releasing hormone (GnRH) that is released from the hypothalamus - GnRH is a peptide hormone consisting of 10 amino acids, it is cleaved from a larger prepropeptide -GnRH is released after puberty in a pulsatile fashion, typically at 90 minute intervals, to stimulate gonadotrophin release from the anterior pituitary gland. -Continuous release of GnRH will lead to a down regulation of GnRH receptors on the surface of gonadotroph cells, this leads to no stimulation of LH/FSH release
what does the hypothalamus release?
-*Anti-diuretic hormone (ADH)*: This hormone increases water absorption into the blood by the kidneys. -*Corticotropin*-releasing hormone (CRH): CRH sends a message to the anterior pituitary gland to stimulate the adrenal glands to release corticosteroids, which help regulate metabolism and immune response. -*Gonadotropin-releasing hormone (GnRH):* GnRH stimulates the anterior pituitary to release follicle stimulating hormone (FSH) and luteinizing hormone (LH), which work together to ensure normal functioning of the ovaries and testes. *Growth hormone-releasing hormone (GHRH)* or growth hormone-inhibiting hormone (GHIH) (also known as somatostain): GHRH prompts the anterior pituitary to release growth hormone (GH); GHIH has the opposite effect. In children, GH is essential to maintaining a healthy body composition. In adults, it aids healthy bone and muscle mass and affects fat distribution. *Oxytocin:* Oxytocin is involved in a variety of processes, such as orgasm, the ability to trust, body temperature, sleep cycles, and the release of breast milk. *Prolactin-releasing hormone (PRH)* or prolactin-inhibiting hormone (PIH) (also known as dopamine): PRH prompts the anterior pituitary to stimulate breast milk production through the production of prolactin. Conversely, PIH inhibits prolactin, and thereby, milk production. *Thyrotropin releasing hormone (TRH)*: TRH triggers the release of thyroid stimulating hormone (TSH), which stimulates release of thyroid hormones, which regulate metabolism, energy, and growth and development.
how do these hormones work?
-As these hormones are lipid soluble, they must be bound to carrier proteins in the blood such as albumin, SHBG and ABP (SHBG produced in the testes). -They act via the classical pathway at nuclear receptors through steroid response elements, but also via the non-classical pathway at cell membrane receptors.
what is the HP portal system?
-Branches from the internal carotid artery provide the blood supply to the pituitary. The superior hypophyseal arteries form the primary capillary plexus that supplies blood to the median eminence. -From this capillary system, the blood is drained in hypophyseal portal veins into the secondary plexus. The peptides released at the median eminence enter the primary plexus capillaries. From there, they are transported to the anterior pituitary via hypophyseal portal veins to the secondary plexus. -The secondary plexus is a network of fenestrated sinusoid capillaries that provide blood to the anterior pituitary. The cells of the anterior pituitary express specific G protein-coupled receptors that bind to the neuropeptides, activating intracellular second messenger cascades that produce the release of anterior pituitary hormones
describe the process of GnRH production.
-GnRH is synthesised in the parvocellular neurones and transported along axons to the capillaries of the primary portal plexus -from here it is transported in portal blood to the anterior pituitary where it acts on the gonadotroph cells to stimulate LH and FSH production. - Kallman syndrome results form a failure of GnRH secreting neurones to migrate during development. This causes infertility as gonadotrophs cannot be secreted
how are women protected from pregnancy once they have had a baby?
-Prolactin levels increase significantly in pregnancy and during breast feeding; this can have a significant impact on the HPG axis as it centrally supresses the release of GnRH (and thus LH and FSH) - This effect is known as lactational amenorrhea and is a natural contraceptive that is up to 98% effective in preventing pregnancy straight after childbirth
how can knowledge of the HPA axis be utilised in medicine?
-The knowledge of the HPA axis can be exploited in many ways. *Hormonal contraception* consists of synthetic progestagens and oestrogens that serve to supress ovulation, thicken the cervical mucus, and thin the endometrium. *Fertility treatment (IVF/ICSI)* requires many oocytes, so ovarian stimulation is used to produce more and their maturation induced with hCG; *the HPG axis can be down*-regulated with GnRH agonists and antagonists or stimulated with FSH. In the treatment of prostate cancer, GnRH agonists can be given to suppress T (testosterone) production.
what is the most potent androgen? what receptors do they act on?
-The most potent androgen is 5α-testosterone (DHT), which is involved in the development and maintenance of the male reproductive system. -The next most potent is testosterone (T), which is involved in the development of secondary sexual characteristics; -then there is androstenedione (A4) that supports sexual function -and finally DHEA that regulates gonadotrophins and supports spermatogenesis. -These all act at AR receptors, which are highly polymorphic.
what is the most potent oestrogen and which receptors do they act at?
-The most potent oestrogen is oestradiol 17β that is involved in the development of secondary sexual characteristics and growth and activity of the mammary glands; this is the dominant oestrogen from puberty to menopause. -The next most potent is oestriol, which stimulates proliferation of the endometrium for progesterone action and is dominant in pregnancy -followed by oestrone that regulates gonadotrophins and is dominant after menopause. -These act at the ERα and ERβ receptors.
what is the most potent progestogen? what receptors do they act on?
-The most potent progestagen is progesterone (P4), which prepares and maintains the uterus for pregnancy. -17α-OHP is the second most potent, and acts in the growth of mammary glands. -The least potent is 20α-OHP, which supresses lactation, has catabolic effects, and regulates the gonadotrophins. -All progestagens act at the PR-A and PR-B receptors, but are able to induce different effects by activating different genes.
What is the role of the pituitary gland? what are the different parts?
-The pituitary gland is a pea-sized gland at the base of the brain, it is from here that a range of hormones are released in response to hypothalamic signals and feedback loops from circulating hormones *Posterior pituitary*: ADH and oxytocin are produced in neuronal cell bodies of the supraoptic and paraventricular nuclei in the hypothalamus. They are then transported along the axons of the hypothalamo-hypophyseal tract to the posterior pituitary, where they are stored. Later they are released into the capillary plexus of the infundibular process which passes the hormones to the posterior hypophyseal portal veins for distribution to target cells in other tissues. *Anterior pituitary*: -Although the hypothalamus does not produce the hormones of the anterior pituitary as in the posterior pituitary, it plays an important role in their production. Releasing hormones synthesized by hypothalamic neurons travel down axons and diffuse into the primary plexus of the hypophyseal portal system. They are then carried by the hypophyseal portal veins to the secondary plexus for distribution to target cells within the anterior pituitary. -All of the anterior pituitary hormones, other than TSH, as well as oxytocin from the posterior pituitary are important in reproductionThe proteins and peptides include ACTH from the corticotrophs, GH from the somatotrophs, and prolactin from the lactotrophs. -The gonadotrophins, LH and FSH, are secreted by the gonadotrophs but there is an additional hormone, hCG, that has a large impact on the HPG axis. As these are glycoproteins, they must signal at the cell surface by binding to GPCRs - LH and hCG are able to act at the same receptor as their β-chains are incredibly similar, with hCG's being slightly longer
describe the difference between central hypogonadism and primary hypogonadism in women?
Clinical problems with the HPG axis can lead to issues with fertility (particularly with women); this can be central hypogonadism in which the problem lies with the pituitary and levels of FSH and LH are low, or primary in which the problem lies with the gonads and levels of FSH and LH are high - GnRH levels are rarely measured due to their pulsatile release and short half-life
what are the main sex steroids released by the gonads? what are their main roles? what other organs produce?
Sex steroids are all derived from cholesterol, via acetate. There are three main families of sex hormones; progestagens are mainly involved in pregnancy, androgens in maleness, and oestrogens in femaleness - These are predominantly secreted from the gonads, but also the adrenal glands, liver and adipose tissue - Prostagens are the largest (21 carbons), these are broken down by enzymes to form androgens (19 carbons), which in turn can be broken down to oestrogens (18 carbons)
what is the definition of oligomenorrhoea and amenorrhoea? when is occupation testing carried out?
Testing for ovulation takes place in the middle of the luteal phase, around day 21, and tests for high levels of progesterone P4. There can be variability in menstrual cycles - Oligomenorrhea is <9 cycles in 12 months - Amenorrhea can be primary (never) or secondary (ceased) and is defined as no bleed in the last 6 months
when is the fertile period?
The fertile period is determined by the viability of the gametes; an oocyte is viable for 24 hours and sperm for 5 days - hence the two must meet in this brief period of time in order for fertilisation to occur. Testing for ovulation takes place in the middle of the luteal phase, around day 21, and tests for high levels of progesterone P4. There can be variability in menstrual cycles
how is the H-P axis different in males and females?
The hypothalamus-pituitary connection in both sexes is essentially the same; differences arise however at the gonads - Male and female gonads produce different sex steroids, as well as some other regulatory factors e.g. inhibin - Regulatory feedback loops are negative in the male, whereas in the female the loops are more complex