Female reproductive endocrinology Flashcards
Reproductive tract hormones are either
o Steroids hormones
o Peptides hormones
Receptors for each type of hormone can be divided into 2 groups:
o Present on cell surface
o Intracellular receptors that interact with lipophilic hormones
Present in serum and tissues in low concentrations
o Implication is that receptors must have high affinity and specificity for ligands (hormones)
How are reproductive tract hormones synthesised and metabolised?
Mainly metabolised in the liver, and to a lesser extent the kidney
Steroid hormones are derived from enzymatic modification of cholesterol
Peptide hormones are synthesised by amino acids
Where are steroid hormones produced?
Mainly synthesised in the gonads, but also in the adrenal gland and placenta during pregnancy
Where are steroid hormones stored?
Lipid soluble and permeable to membranes so are not stored, but synthesised then released
o This makes them quite fast acting
Describe the synthesis of progesterone
Progesterone is formed early on in the synthetic pathway
o Cholesterol is converted to pregnenolone, and then to progesterone
o Converted to eventually form either
Aldosterone
Cortisol
Testosterone
Oestrogens (oestrone and oestradiol)
Aromatase: converts androgens in the form of testosterone (or androstenediol) oestrogens
o Other androgens are very similar to testosterone, and will have similar effects on the male
reproductive tract
Describe the formation of oestrogens
There are two different types of oestrogen
Circulating oestrogens are a mix of oestrone and oestradiol
o Oestrone
secreted directly from ovary
or converted from androstenedione (granulosa cells contain aromatase, which can
convert the androgens to oestrogen)
o Oestradiol is produced by the ovary, derived by:
Direct synthesis in developing follicles; follicles contain aromatase
or through conversion of oestrone
Involved in the development of female secondary sex characteristics
o Oestrogen drives the development of the female reproductive tract
Describe the production of androgens
The ovary produces androstenediol, dehydroepiandrosterone (DHEA) and small amounts of testosterone
o Testosterone is produced is mainly for conversion to oestrogens
NB: Adrenal cortex contributes:
o approximately half the daily production of androstenedione and DHEA
o essentially all of the sulphated form of DHEA (DHEAs)
The adrenal gland is an important source of androgens in females
o With hormonal imbalance in women, it is important to check adrenal gland function as this can
be a source of problems
What is progestogen?
(Progestins)
Synthesised from cholesterol via pregnenolone
Produced primarily in corpus luteum of ovary, but also in the adrenal glands and in the placenta during
pregnancy
Important in:
o Endometrial development (especially in second half of the menstrual cycle)
o Smooth muscle control
o Maintenance of pregnancy - placenta
Early pregnancy failure is often due to lack of progesterone
o Mammary gland development
What is Congenital Adrenal Hyperplasia
21-hydroxylase deficiency Deficiency in 11 β-hydroxylase activity o Less common (5-8% cases) Hormone synthesis is driven in a different direction Individuals have: o ambiguous genitalia, o precocious puberty o anovulation often the first time the condition is noticed o hirsutism
hirsutism:
condition of unwanted, male-pattern hair growth in women. Hirsutism results in excessive amounts of dark, course hair on body areas where men typically grow hair — face, chest and back
What is Aromatase deficiency
Prevents oestrogen synthesis
Ambiguous genitalia because oestrogen is
important in driving the development of the
external genitalia
What is Aromatase excess
Excessive conversion of androgens to oestrogens
Feminisation of male genitalia
Describe the hypothalamic-pituitary-ovarian axis
The hypothalamus secretes gonadotrophin releasing hormone (GnRH) which stimulates the anterior
pituitary to release follicle stimulating hormone (FSH) and luteinising hormone (LH)
The ovary (and placenta) respond to levels of the gonadotrophins and secrete steroid sex hormones
Describe the role of the hypothalamus in the HPO axis
Neurosecretory cells produce GnRH
GnRH – 10 amino acid peptide hormone with short half life
o GnRH is important in preparing the body for the onset of
puberty
Secreted into the portal vessels in a pulsatile manner
Activates its receptor (GnRHR) within the anterior pituitary, which
stimulates release of gonadotrophins
Describe the role of the Ovaries in the HPO axi
Ovaries (and placenta) represent the 3 rd level of hormonal control
Levels of FSH and LH stimulate and trigger follicle maturation and regulate steroid hormone production in the ovary
These hormones act on target tissues in the reproductive tract
o Mainly the uterus, cervix and vagina
Describe the role of the Pituitary gland in the HPO axi
2 nd level of hormonal control of reproduction
Anterior pituitary secretes peptide hormones
o follicle stimulating hormone (FSH)
o luteinising hormone (LH)
Travel through the blood stream and act on the ovary
Posterior pituitary secretes oxytocin
o Involved in childbirth and lactation
Describe the action of FSH – follicle stimulating hormone
Initiates recruitment of follicles
o Woman is born with her life supply of eggs, surrounded by supporting (follicular) cells
o FSH chooses the cohort of cells that are going to mature selected for further growth
o Stimulates follicles to grow, which increase in number and size
Supports growth of the follicle, especially the granulosa cells
o Leaves the resting state
o As the follicle enlarges, the cells within it differentiate into two different populations
Granulosa cells express the enzyme aromatase
Theca cells (interna and externa) release androgens
o As the follicle grows, it releases more oestrogen
Describe the action of LH – luteinising hormone
Supports theca cells
Receptors for LH are only expressed on maturing follicle
o LH therefore only acts on mature (secondary and above) follicles
Once there is enough follicular growth and the oocyte is ready to be ovulated, an LH surge triggers ovulation
What are the phases of teh ovarian cycle?
o a preovulatory follicular phase
all events before ovulation
o A postovulatory luteal phase
All events after ovulation, time when the corpus luteum is formed
What are the phases in theuterine cycle?
o proliferative phase
o secretory phase
> glands of the endometrium are very active at this point, secrete a lot of carbohydrates
o menstrual phase
> endometrium breaks down and is shed if fertilisation doesn’t occur
Describe FSH during the follicular phase
FSH levels relatively high and quite steady as the follicle is growing
o They are not peaking, as you need just enough FSH to stimulate follicular growth
Mini peak at the time of ovulation FSH is stored up and is then released when its not being used
anymore
FSH makes follicles grow, and growing follicles secrete oestrogen
o Secondary and tertiary follicles means lots of granulosa and thecal cells = peak of oestrogen
before ovulation (mid-cycle)
Describe LH during the follicular phase
LH surge drives ovulation
o Matures the thecal cells
o Levels increase dramatically 36 hours before ovulation pushes oocyte to ovulate
o Levels then return to normal
Describe progesterone during the follicular phase
o Second half of the cycle
o After ovulation, corpus luteum produces all the progesterone required to initiate pregnancy
o Makes endometrium secretory
Keeps glands full of secretions and keeps endometrium spongy
o If fertilisation doesn’t occur, the corpus luteum dies in the absence of hCG
o Corpus albicans = degenerating corpus luteum
Describe the features of the follicular phase
Varies in length (10-14 d) depending on the length of a woman’s cycle
Characterised by growth of dominant follicle
o This is a continual process, about 20-30 are selected for growth at any single time
o There will be follicles at different stages of development at any one time
Primordial follicle (resting follicles)
Primary follicle
Secondary follicle has an antrum (fluid filled space)
Graafian follicle = tertiary follicle; larger secondary follicle (fluid increases)
Fluid helps push the oocyte out at ovulation
Progesterone production is low
Oestrogen is rising due to conversion of androgens to oestrogens via aromatase (by follicles)
Describe the development of the primary follicle from the primordial follicle
Surrounding cells of the ovary release signals to recruit oocytes near that area
o BMP-4, BMP-7 from stromal cells act on oocyt
o The oocyte acts on these signals, producing its own factors which then act on stromal cells (KT ligand)
Stromal cells send out signals that act on the follicle cells and tell oocyte/follicle cells to start growing
Primordial follicle
o Surrounded by only one layer of follicular cells
Primary follicle
o Start to get more than one layer of follicular cells
o Ring of red staining around edge of oocyte = zona pellucida
Contains receptors for sperm binding
Describe the development of the secondary follicle
FSH secretion increases slightly, stimulating further growth of recruited follicles.
Circulating LH levels increase slowly, beginning 1 to 2 days after the increase in FSH.
Theca develops – follicle gains an independent blood supply
Granulosa cells develop FSH, oestrogen and androgen receptors
Describe the hormonal changes following the
development of the secondary follicle
As the antrum increases in size, the oocyte is pushed to the side of the follicle, preparing it for ovulation
Recruited follicles increase production of oestradiol via conversion of androgens produced in the theca
interna into oestrogens by the granulosa cells – aromatase
Stimulates LH and FSH synthesis but inhibits their secretion
o LH/FSH are mainly being stored
FSH levels decrease as ovulation approaches
o Oestradiol inhibits FSH and LH
o FSH and LH levels diverge partly because oestradiol inhibits secretion more than LH secretion.
Developing follicles produce the hormone inhibin
o inhibits FSH secretion but not LH secretion.
Levels of oestrogen, particularly oestradiol, increase exponentially
o Important for feeback!
Describe feedback in the follicular phase
Negative feedback throughout most of the menstrual cycle
Once oestrogen and progesterone levels are high enough, production of GnRH, FSH and LH is inhibited via negative feedback on the hypothalamus and pituitary
This is the case until mid-cycle
NB: follicle growth causes an exponential increase in oestrogen due
to production by follicles around days 12-14
o Switches off negative feedback and changes to positive feedback
o Stored LH is released by the anterior pituitary => this
causes ovulation
Inhibin released by the ovary inhibits FSH production
Describe the uterine changes in response to hormones in the proliferative phase
Oestrogens from the ovary act on the endometrium Thickening of the stroma Elongation of uterine glands Growth of the spiral arteries
Describe ovulation
Occurs mid cycle ~ day 14
Towards the end of the proliferative phase, rising oestrogens levels increase responsiveness of pituitary
to GnRH, causing a surge in hypothalamic secretion of GnRH
Oestradiol levels peak and progesterone levels begin to increase.
High levels of oestradiol trigger LH secretion by gonadotropes (positive feedback).
Stored LH is released in massive amounts (LH surge), usually occurs over 36-48 h, with a smaller increase
in FSH (which was also stored)
Describe the homonal changes after ovulation
After ovulation, oestradiol decreases, but progesterone continues to increase.
The LH surge also stimulates enzymes that initiate breakdown of the follicle wall
This causes release of the mature oocyte within about 16 to 32 h.
The LH surge also triggers completion of the first meiotic division of the oocyte within about 36h of
ovulation.
o Helps release oocyte from meiotic arrest
What is the luteal stage?
The length of this phase is the most constant, averaging 14 days in most women
Formation of the corpus luteum from the follicle
Describe changes in progesterone during the luteal phase
The corpus luteum secretes primarily progesterone in increasing quantities
o peaks at about 6 to 8 days after ovulation
o 21-day progesterone test (highest level of progesterone is 6-8 days after ovulation)
o High levels of progesterone suggest healthy ovulation
o Good test for ovulation
Progesterone stimulates development of the secretory endometrium
Glands of endometrium are much larger, much more coiled and tortuous
o vessels are very well developed to make the uterus as hospitable as possible
Corpus luteum is very yellow because it contains luteal cells
o These produce fat
Describe the hormonal changes during the luteal phase
Main hormone driving the second half of the cycle is progesterone
Because levels of circulating oestradiol, progesterone, and inhibin are high during most of the luteal
phase, LH and FSH levels decrease.
o This switches negative feedback back on
o NB: positive feedback only occurs around days 12-14
Oestradiol and progesterone levels decrease late in this phase.
If implantation occurs, the corpus luteum does not degenerate but remains, supported by human
chorionic gonadotropin produced by the embryo.
In this case, hormone levels would stay very high to support the pregnancy
Describe the hormonal changes during the menstruation phase
Inhibin directly inhibits the secretion of gonadotrophins
o Especially inhibits FSH
o However, LH is also decreased
This results in the regression of the corpus luteum and a reduction in the secretion of progesterone
o Inhibin pushes regression of corpus luteum
Describe the changes in the endometrium during the menstruation phase
Massive leukocyte infiltration of endometrium
Constriction and breakdown of spiral arteries
o Blood is unable to pass through the spiral arteries
o Causes ischemia in the surrounding stroma of the endometrium
o Surrounding tissue dies off
o Once the tissue has died off, this releases the pressure off the arteries and backed-up blood
flows again
o The blood “washes” the dead endothelial lining away => menstrual period
o This loss happens in patches across the endometrium => this is why menstruation lasts several
days
Describe the histological appearances during the menstruation phase
Less glandular material during this phase
NB: the basal layer of endometrium remains => responsible for re-growing the endometrium
Only stratum functionalis is lost
Describe the changes in the vagina during the cycle
Early follicular phase:
- oestrogen is low
- vaginal epithelium is thin and pale
Late follicular stage
- oestrogen rises
- squamous cells mature, causing epithelial thickening
Luteal phase:
- mature squamous cells shed as cellular debris
Describe the changes in the cervix during the cycle
Late follicular stage
- oestrogen rises
- increased cervical vascularity and water mucus => allows sperm passage
- external os openes slightly, fills with mucus
Luteal phase:
- progesterone levels increase
- thickens cervical mucus, reduces elasticity
Describe the mechanism of action of hormonal contraception
Combinations of oestrogens and progestins or continuous progestin therapy
Exert their contraceptive effect largely through selective inhibition of pituitary function resulting in
inhibition of ovulation.
Maintaining hormones at the level of negative feedback
The continuous use of progestins alone does not always inhibit ovulation.
o Change in the cervical mucus, in the uterine endometrium, and in motility and secretion in the
uterine tubes.
o Change how cilia beats prevents eggs reaching the uterus
What is polycystic ovarian syndrome?
Common endocrine abnormality
Clinical presentation
o Infertility (not always)
o No ovulation
o Lack of menses (increased androgens)
o Weight gain, hirsutism, acne
o Complex hormonal imbalance
o “String of pearls appearance” of cysts on ultrasound of ovary
Complex hormonal imbalance LH/FSH secretion is ‘out of balance’
No negative feedback => menstrual cycle is never established properly
Continuous oestrogen production leads
to elevated LH:FSH ratio
o >2:1 diagnostic
Increase LH leads to increased androgen
production
o Interconversion of hormones
o Impacts adipose tissue =>insulinresistance
o Often treated with metformin
and diabetic-controlled diet
