The menstrual cycle and its hormonal control

Question 1

Define menarche. Is this mainly hormonal or ovarian ?

Answer 1

Occurs towards the end of puberty and marks the beginning of potential fertility. (maturation of GnRH pulsatility so primarily hypothalamic)

Question 2

Define menopause. Is this mainly hormonal or ovarian ?

Answer 2

Occurs about 45 – 55 y (average 51 yrs ) and marks the end of natural fertility.
“Exhaustion” of primordial follicles so primarily ovarian

Question 3

Define Premature Ovarian Failure (POF). Are there any treatments for it ?

Answer 3

– Premature Ovarian Failure (POF)
Menopause can occur in women under the age of 40 (idiopathic, autoimmune disorders, genetic disorders such as Fragile X, chemotherapy, radiation)
– Symptoms can be treated with oestrogen replacement (hormone replacement therapy – HRT)

Question 4

Identify the main phases/events of the menstrual cycle;

Answer 4

-Lasts around 28 days.
-Starts with follicular phase, lasting approximately 14 days.
This includes mences (uterine bleeding) from day 1 to approx day 5 (first day of menstrual bleeding denotes day 1 of the menstrual cycle)
-Around day 14, ovulation occurs.
-Following ovulation, luteal phase occurs, also lasting about 14 days.

Question 5

Identify the main ovarian events occurring during the menstrual cycle.

Answer 5

In follicular phase:

• Multiple follicles develop, from day 1 to day 7
• Around day 7, one follicle becomes dominant
• From day 7 to approx day 14, dominant follicle matures

In luteal phase:

• Corpus lutem functions, from day 14 (following ovulation) to approx day 25
• Corpus lutem degenerates around days 25-28

Question 6

Describe the main hormonal patterns of FSH, LH, estrogen, progesterone, and inhibin in the menstrual cycle.

Answer 6

• FSH: Increases in early part of follicular phase, then steadily decreases throughout remainder of cycle EXCEPT small midcycle peak.
• LH: Constant during most of follicular phase, then large midcycle increase (LH surge) peaking ~18h before ovulation. Then rapid decrease with further slow decline during the luteal phase.
• Oestrogen: Low and stable for 1st week, increases rapidly in 2nd weeks, starts to decline before LH peak. Then second increase due to corpus luteum in last few days of cycle.
• Progesterone: Low level due to ovary release during follicular phase with small increase just before ovulation. Soon after ovulation, large increase due to CL release, then similar pattern to oestrogen.
• Inhibin: Similar pattern to oestrogen ie increases in late follicular phase, remains high during luteal phase, decreases as corpus luteum degenerates.

Question 7

Describe the feedback effects of ovarian hormones.

Answer 7

1. Oestrogen, in low plasma concentrations, causes the anterior pituitary to secrete less FSH and LH in response to GnRH and also may inhibit the hypothalamic neurons that secrete GnRH.
   RESULT: -ve feedback inhibition of FSH and LH secretion during the early and middle follicular phase.
2. Inhibin acts on the pituitary to inhibit the secretion of FSH.
   RESULT: -ve feedback inhibition of FSH secretion throughout the cycle.
3. Oestrogen, when increasing dramatically, causes anterior pituitary cells to secrete more LH and FSH in response to GnRH. Oestrogen can also stimulate the hypothalamic neurons that secrete GnRH.
   RESULT: +ve feedback stimulation of the LH surge, which triggers ovulation.
4. High plasma concentrations of progesterone, in the presence of oestrogen, inhibit the hypothalamic neurons that secrete GnRH.
   RESULT: -ve feedback inhibition of FSH and LH secretion and prevention of LH surges during the luteal phase and pregnancy.

Question 8

FSH

• When does it reach its max ?
• What is its function ?

Answer 8

FSH
• MAX: The concentration of FSH in the blood rises to its maximum during the follicular phase of the menstrual cycle.
• FUNCTION: In the first week of the follicular phase it stimulates the growth of medium sized follicles. Granulosa cells of the ovary express FSH receptors during the follicular phase of the menstrual cycle, so FSH stimulates Granulosa cells to androstenedione to oestrodiol 17β.

Question 9

What is the homologous structure of Granulosa cells in males ?

Answer 9

Granulosa cells are homologous to the Sertoli cells of the testis.

Question 10

What is the homologous structure of Theca cells in males ?

Answer 10

Theca cells are similar to Leydig cells in males.

Question 11

LH

• Describe its levels in the menstrual cycle
• What is its function ?

Answer 11

LH
• MAX: The levels of LH vary during the follicular and secretory phases of the menstrual cycle. 12h before ovulation LH rises dramatically (stimulated by an increasing rate of secretion of oestrodiol-17β)
• FUNCTION: during the secretory phase it stimulates steroid hormone synthesis by the corpus luteum + stimulates androstenedione synthesis by Thecal cells.

Question 12

Describe the main events occurring to the endometrium throughout the uterine phases.

Answer 12

• In menstrual phase, breakdown of endometrium thickness.
• In proliferative phase, builds up again.
• In secretory phase, no breakdown of build up, but significant amount of development in walls of tissue (secretory phase includes an ischemic phase at the very end of it, before menstrual phase)

Question 13

Describe the hormonal control of estrogen synthesis. Which phase does this occur in ?

Answer 13

Control of oestrogen synthesis during the early and middle follicular phases:

• GnRH in hypothalamus secreted, stimulating anterior pituitary to secrete FSH and LH
• LH acts on theca cells of follicle, which therefore synthesise androgens (mainly androstenedione)
• Androgens then diffuse across BM to granulosa cells, also surrounding oocytes.
• Then, FSH acts on granulosa cells to convert androgens to estrogens (e.g. androstenedione to oestrodiol 17β), which affects reproductive tract and organs
• Granulosa cells also produce Inhibin
• Inhibin and estrogens have negative feedback effect (Inhibin mainly on FSH, estrogen on FSH, LH, and GnRH)

Control of estrogen synthesis in later follicular phases:
• In the mid-cycle, shift from –ve to +ve feedback.
– Caused by upregulation of receptors (e.g. GnRH in anterior pituitary) when oestrogen plasma levels are rapidly increased (through secretion by dominant follicle).
– Estrogens (and progestins) begin to stimulate increase in GnRH, LH, and FSH
– Results in LH and FSH surge prior to ovulation.

Question 14

When does LH surge occur ? What is its result ?

Answer 14

At later parts of follicular phase

Increased plasma LH triggers ovulation (resumption of
meiosis) and formation of corpus luteum.

Question 15

Is inhibin involved in the mid cycle shift from negative to positive feedback ?

Answer 15

No, it performs negative feedback back to FSH regardless of time of cycle

Question 16

Which type of cell is LH action mediated by, during the later stages of the follicular phase ?

Answer 16

Actions of LH are mediated via granulosa cells (?)

Question 17

Identify the effects of LH surge on ovarian function.

Answer 17

1. The 1° oocyte completes its first meiotic division and undergoes cytoplasmic changes that prepare the ovum for implantation should fertilisation occur. These LH effects on the oocyte are mediated by messengers released from the granulosa cells in response to LH.
2. Antrum size (fluid volume) and blood flow to the follicle increase markedly.
3. The granulosa cells begin releasing progesterone and decreasing the release of oestrogen, which accounts for the midcycle decrease in plasma oestrogen concentration and the small rise in plasma progesterone just before ovulation.
4. Enzymes and prostaglandins, synthesized by the granulosa cells, breakdown the follicular-ovarian membranes. These weakened membranes rupture, allowing the oocyte and its surrounding granulosa cells to be carried into the surface of the ovary.
5. The remaining granulosa cells of the ruptured follicle (along with the theca cells of that follicle) are transformed into the corpus luteum, which begins to release progesterone and oestrogen.

Question 18

Identify the functions of the granulosa cells.

Answer 18

1. Nourish oocyte.
2. Secrete chemical messengers that influence the oocyte and theca
   cells.
3. Secrete antral fluid.
4. Are the site of action for oestrogen and FSH in the control of the follicle development during early and middle follicular phases.
5. Express aromatase, which converts androgen (from theca cells) to oestrogen.
6. Secrete inhibin, which inhibits FSH secretion via an action on the pituitary.
7. Are the site of action for LH induction of changes in the oocyte and follicle culminating in ovulation and formation of the corpus luteum.

Question 19

Describe the main hormonal events of the luteal phase.

Answer 19

• Suppression of LH and FSH in luteal phase (negative feedback by inhibin to FSH, and by estrogen and progestins to GnRH, FSH, LH)
• If no implantation:
– hCG does not appear in blood
– CL dies
– progesterone and oestrogen decrease
– therefore, menstruation occurs and next MC begins (and FSH and LH increase enough for new follicle growth, thanks to progesterone and estrogen decrease)
• If yes implantation:
Human chorionic gonadotrophin produced by placenta maintains corpus luteum which continues to secrete progesterone. Since progesterone remains high, then levels of LH and FSH will be suppressed and subsequent ovulation will not occur.

Question 20

What are the main events of the proliferative phase of the uterine cycle ? Identify the hormones involved.

Answer 20

• Menstrual flow ceases.
• Under influence of oestrogen, endometrium thickens.
– Growth of underlying smooth muscle (myometrium) also occurs.
– Also causes the cervical mucus to be readily penetrable by sperm
• Synthesis of receptors for progesterone in endometrial cells also occurs.
• Lasts for ~10 days until ovulation.

Question 21

Describe the histology of the proliferative phase of the uterine cycle.

Answer 21

• Repair of lining epithelium after menstruation
• Proliferation and thickening of stroma
• Simple test tube shaped glands
• Induction of synthesis of intracellular receptors for progesterone (i.e. it primes the uterus for later progesterone secretion)
• Contractility and excitability of the myometrium increases
• Cervical mucus becomes readily penetrable by sperm (thanks to estrogen)

Question 22

What are the main events of the secretory phase of the uterine cycle ? Identify the hormones involved.

Answer 22

• Estrogen primed endometrium increases secretory activity under influence of progesterone.

• Endometrial glands:
– become coiled, filled with glycogen, blood vessels become more numerous, enzymes accumulate in glands and connective tissue.
– All to make endometrium a hospital environment for implantation and nourishment of developing embryo.

• Cervical mucus made relatively impenetrable to sperm by progesterone
• Uterine contractions inhibited by progesterone

Question 23

When does the secretory phase of the uterine cycle begin ?

Answer 23

• Begins soon after ovulation.

Question 24

Describe the histology of the secretory phase of the uterine cycle.

Answer 24

• Proliferation/thickening of stroma
• Spiral arteries develop alongside complex,
hacksaw shaped glands
• Secretion in the glands is rich in glycoprotein sugars and amino acids
• Enlargement of myometrial cells but depressed overall excitability

Question 25

Which hormone is the proliferative phase of the uterine cycle dominated by ?

Answer 25

Dominated by estradiol 17β)

Question 26

Which hormone is the secretory phase of the uterine cycle dominated by ?

Answer 26

Dominated by Progesterone

Question 27

State the duration of each phase of the uterine cycle.

Answer 27

Menstrual: 5 days (but can last 2 to 7)
Proliferative: 11 days
Secretory: 12 days

Question 28

Describe the histology of the ischemic phase of the uterine cycle.

Answer 28

Loss of steroid support:

• Constriction of spiral arteries
• Ischemia and collapse of endometrium
• Separation of basal and functional layers
• Functional layer is shed as menstrual bleeding Increase in neutrophils

Question 29

Describe the histology of the menstrual cycle of the uterine cycle.

Answer 29

• Bleeding without clotting: endogenous fibrinolytic activity
• Dysmenorrhoea

Question 30

State the normal V of blood loss in a cycle.

Answer 30

30 -80mls normal

Question 31

Identify the main effects of estrogen in the body.

Answer 31

1. Stimulates growth of ovary and follicles (local effects).
2. Stimulates growth of smooth muscle and proliferation of epithelial linings of reproductive tract (including proliferation of the endometrium). In addition:
   a) Fallopian tubes: Increases contractions and ciliary activity (i.e. increased motility)
   b) Uterus: Increases myometrial contractions and responsiveness to oxytocin. Stimulates secretion of abundant, watery cervical mucus. Prepares endometrium for progesterone’s actions by inducing progesterone receptors.
   c) Vagina: Increases layering of epithelial cells.
3. Stimulates external genitalia growth, particularly during puberty.
4. Stimulates breast growth, particularly ducts and fat deposition during puberty.
5. Stimulates female body configuration development during puberty: narrow shoulders, broad hips, female fat distribution (deposition on hips and breasts).
6. Stimulates fluid secretion from lipid (sebum)-producing skin glands (sebaceous glands). (Is an “anti-acne” effect opposing the acne- producing effect of androgen).
7. Stimulates bone growth and ultimate cessation of bone growth (closure of epiphyseal plates); protects against osteoporosis; does not have an anabolic effect on skeletal muscle.
8. Vascular effects (deficiency produces “hot flashes”)
9. Has feedback effects on hypothalamus and anterior pituitary.
10. Stimulates prolactin secretion but inhibits prolactin’s milk-inducing action on the breasts.
11. Protects against atherosclerosis by effects on plasma cholesterol, blood vessels, and blood clotting.

Question 32

Identify the main effects of progesterone.

Answer 32

1. Converts the oestrogen-primed endometrium to an actively secreting tissue suitable for implantation of an embryo.
2. Induces thick, viscous cervical mucus.
3. Decreases contractions of fallopian tubes and
   endometrium.
4. Decreases proliferation of vaginal epithelial cells.
5. Stimulates breast growth, particularly glandular tissue.
6. Inhibits milk-inducing effects of prolactin.
7. Has feedback effects on hypothalamus and anterior pituitary
8. Increases body temperature

Question 33

Where is estrogen, and progesterone, produced ?

Answer 33

Both produced by the ovary

Question 34

Define:

• Meno
• Oligomenorrhoea
• Metrorrhagia
• Dysmenorrhoea
• Polymenorrhoea
• Amenorrhoea

Answer 34

Meno – menstruation
•  Oligomenorrhoea - infrequent light periods 
•  Metrorrhagia - irregular bleeding
•  Dysmenorrhoea - painful periods
•  Polymenorrhoea – frequent periods
•  Amenorrhoea - no periods

Question 35

What is the main cause of dysmenorrhea ? Are there any accompanying symptoms to dysmenorrhea ?

Answer 35

Main cause is overproduction of prostaglandins produced by endometrium in response to decrease in plasma oestrogen and progesterone, leading to excessive uterine contractions.

• Prostaglandins can affect smooth muscle elsewhere and may account form some of the systemic symptoms that sometimes accompany cramps eg nausea, vomiting, headache.

Question 36

Describe PMS. Why does this happen ?

Answer 36

♦ "Symptoms that occur between ovulation and the onset of menstruation". May include: 
•  anxiety
•  mood swings
•  tiredness
•  irritability
•  depression
•  a loss in confidence
•  clumsiness
•  headaches
•  feeling bloated
•  a change in appetite
•  joint pain
•  tender enlarged breasts 
•  abdominal pain

♦ More serious is premenstrual dysphoric disorder (PMDD). Can be temporarily disabling.

♦ Progesterone has anxiolytic effect. Some of the psychological effects may therefore be due to falling progesterone levels at the end of the cycle.

Question 37

What are the main causes of amenorrhoea ?

Answer 37

• Primary
– Anatomical/ congenital abnormality e.g. underdevelopment or absence of uterus/vagina
– Genetic e.g. Turner’s syndrome

•  Secondary
–  Pregnancy
–  Lactation
–  Exercise/ Nutrition
–  Menopause
–  Polycystic Ovarian Syndrome
–  Iatrogenic (surgery, medication)

Question 38

Identify the main effects of amenorrhoea.

Answer 38

1) Estrogen deficiency symptoms
- Hot flushes (flashes)
- Vaginal dryness

2) Loss of bone mineralisation (due to lack of estrogen)
- Reduction in peak bone mass attained
- Osteopenia/ osteoporosis

Question 39

Describe the female athlete triad.

Answer 39

Ideally, would wish for:

• Optimal energy availability (which contributes to the two aspects below)
• Eumenorrhea (which contributes to the aspect below)
• Optimal bone health

In certain athletes, may be periods (e.g. in high intensity training cycles) or it can be constantly, that:

• Low energy availability (could be due to eating disorder)
• Functional hypothalamic amenorrhoea (due to ^)
• Osteoporosis (due to ^ and ^^)

Question 40

Does the female athlete triad apply to men ?

Answer 40

No, because do not experience periods. HOWEVER:

RED-S (Relative energy deficiency in sports) involves both. Female athlete triad included in that as well, but it does involve other components which involve both men and women.

Question 41

Describe why lactational amenorrhoea occurs.

Answer 41

i.e. mother is breastfeeding, and she does not have any periods whilst she is breastfeeding

• Mother bears all metabolic costs of pregnancy and lactation.
• In a marginal environment, for the benefit of the baby that she is breastfeeding, need a mechanism to prevent pregnancy during lactation (so she can support the metabolic cost of the lactation and not have to be supporting a pregnancy as well)
• Child survival (in this marginal environment) is related to birth spacing.
• ‘Natural’ breast feeding involves feeding ad lib and with baby sleeping with mother and feeding through the night.
• Women who breast feed ‘naturally’ may experience lactational amenorrhoea which decreases likelihood of pregnancy until weaning occurs of the first offspring has occurred, or at least until breastfeeding has reduced a significant amount