Female reproductive endocrinology

Question 1

Reproductive tract hormones are either

Answer 1

o Steroids hormones

o Peptides hormones

Question 2

Receptors for each type of hormone can be divided into 2 groups:

Answer 2

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)

Question 3

How are reproductive tract hormones synthesised and metabolised?

Answer 3

 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

Question 4

Where are steroid hormones produced?

Answer 4

Mainly synthesised in the gonads, but also in the adrenal gland and placenta during pregnancy

Question 5

Where are steroid hormones stored?

Answer 5

Lipid soluble and permeable to membranes so are not stored, but synthesised then released
o This makes them quite fast acting

Question 6

Describe the synthesis of progesterone

Answer 6

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

Question 7

Describe the formation of oestrogens

Answer 7

 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

Question 8

Describe the production of androgens

Answer 8

 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

Question 9

What is progestogen?

Answer 9

(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

Question 10

What is Congenital Adrenal Hyperplasia

Answer 10

 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

Question 11

hirsutism:

Answer 11

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

Question 12

What is Aromatase deficiency

Answer 12

 Prevents oestrogen synthesis
 Ambiguous genitalia because oestrogen is
important in driving the development of the
external genitalia

Question 13

What is Aromatase excess

Answer 13

 Excessive conversion of androgens to oestrogens

 Feminisation of male genitalia

Question 14

Describe the hypothalamic-pituitary-ovarian axis

Answer 14

 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

Question 15

Describe the role of the hypothalamus in the HPO axis

Answer 15

 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

Question 16

Describe the role of the Ovaries in the HPO axi

Answer 16

 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

Question 17

Describe the role of the Pituitary gland in the HPO axi

Answer 17

 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

Question 18

Describe the action of FSH – follicle stimulating hormone

Answer 18

 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

Question 19

Describe the action of LH – luteinising hormone

Answer 19

 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

Question 20

What are the phases of teh ovarian cycle?

Answer 20

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

Question 21

What are the phases in theuterine cycle?

Answer 21

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

Question 22

Describe FSH during the follicular phase

Answer 22

 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)

Question 23

Describe LH during the follicular phase

Answer 23

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

Question 24

Describe progesterone during the follicular phase

Answer 24

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

Question 25

Describe the features of the follicular phase

Answer 25

 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)

Question 26

Describe the development of the primary follicle from the primordial follicle

Answer 26

 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

Question 27

Describe the development of the secondary follicle

Answer 27

 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

Question 28

Describe the hormonal changes following the

development of the secondary follicle

Answer 28

 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!

Question 29

Describe feedback in the follicular phase

Answer 29

 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

Question 30

Describe the uterine changes in response to hormones in the proliferative phase

Answer 30

 Oestrogens from the ovary act on the
endometrium
 Thickening of the stroma
 Elongation of uterine glands
 Growth of the spiral arteries

Question 31

Describe ovulation

Answer 31

 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)

Question 32

Describe the homonal changes after ovulation

Answer 32

 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

Question 33

What is the luteal stage?

Answer 33

 The length of this phase is the most constant, averaging 14 days in most women
 Formation of the corpus luteum from the follicle

Question 34

Describe changes in progesterone during the luteal phase

Answer 34

 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

Question 35

Describe the hormonal changes during the luteal phase

Answer 35

 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

Question 36

Describe the hormonal changes during the menstruation phase

Answer 36

 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

Question 37

Describe the changes in the endometrium during the menstruation phase

Answer 37

 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

Question 38

Describe the histological appearances during the menstruation phase

Answer 38

 Less glandular material during this phase
 NB: the basal layer of endometrium remains => responsible for re-growing the endometrium
 Only stratum functionalis is lost

Question 39

Describe the changes in the vagina during the cycle

Answer 39

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

Question 40

Describe the changes in the cervix during the cycle

Answer 40

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

Question 41

Describe the mechanism of action of hormonal contraception

Answer 41

 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

Question 42

What is polycystic ovarian syndrome?

Answer 42

 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