Sex Hormones

Question 1

When does the reproductive axis ‘awaken’ / ‘activate’?

Define puberty: (what are the changes that occur during puberty?)

Answer 1

Puberty

Maturation of the reproductive organs - start secreting reproductive hormones (sex steroids - oestradiol, testosterone) resulting in development of secondary sexual characteristics which gives them the capability to reproduce

Question 2

What is the first sign of puberty in females?

What is Tanner staging in females?

What is the first sign of puberty in males?

What is Tanner staging in males?

Answer 2

Thelarche - breast development, which is the first visible change when a girl hits puberty

Tanner grades breast development from stages I to V, I = prepubertal, V = adult

Testicular volume

Tanner grades testicular volume from stages I to V, I = 1-2ml (prepubertal), V = >15ml (adult)

Question 3

What medical instrument can be used to measure testicular volume in a clinical setting?

What is a sign of puberty in both sexes?

What is Tanner staging for this?

Answer 3

Orchidometer

Pubarche - pubic hair development

Tanner grades pubarche from stages I - V, I = no pubic hair (prepubertal), V = full pubic hair (adult)

Question 4

What is meant by the suffix ‘arche’?

Therefore what are the definitions of: gonadarche, thelarche, menarche, spermarche, adrenarche, and pubarche

Answer 4

Onset of

Gonadarche - activation of gonads via HPG axis; thelarche - onset of breast development; menarche - onset of the menstrual cycle; spermarche - onset of spermatogenesis; adrenarche - onset of adrenal androgen production (starts 2 years before gonadarche); pubarche - onset of pubic hair development

Question 5

Which hormones in each of the sexes cause secondary sexual characteristics?

What are the secondary sexual characteristics in males and females?

What can changes in sweat gland composition cause?

Answer 5

Female - oestradiol; Male - testosterone

Female - breast development, pubic and axillary hair growth, changes in sweat gland composition, changes in the external genitalia; male - deepening of voice, pubic, axillary and facial hair growth, increased testicular volume, increase in muscle mass / body composition, changes in sweat gland composition, changes to external genitalia

Oiliness of skin / acne

Question 6

When does puberty start in boys and girls?

What are the first and late signs in the start of puberty for girls and boys?

Answer 6

Girls: 8-13 years, breast development first, then pubic hair tanner begins (about a year later)

Boys: 9-14 years, testicular development first, then pubic hair begins (about a year later)

Girls: 1st sign = thelarche, Late sign = menarche

Boys: 1st sign = testicular development

Question 7

What is meant by the term ‘growth spurt’?

Fill on the axis for girls and boys, the start of adrenarche, growth spurts, menarche (in girls), sparmarche (in boys), breast / testes development, pubic hair development:

Answer 7

Growth spurt - peak acquisition of height (earlier in girls than boys)

Everything in boys happens around 1-2 years later than in girls, and whilst menarche begins when breast development hits tanner 5, spermarche begins when testes development hits tanner 4

Question 8

What is DHEA?

When does DHEA production begin?

What are the other hormonal changes that occur in girls and boys during puberty?

Answer 8

An adrenal androgen

Around 2 years before the first signs of puberty begin

Girls - DHEA, LH, FSH and oestradiol levels increase

Boys - DHEA, testosterone levels increase

Question 9

What is the HPG axis?

How must GnRH be released in order for the HPG axis to be active?

How does GnRH secretion change from the foetal stage to adulthood? Why do they take place?

Answer 9

Hypothalamic-pituitary-gonadal axis - GnRH released from the hypothalamus in a pulsatile fashion, travels via portal system to anterior pituitary gland and stimulates gonadotrophs to release gonadotrophins (LH and FSH), gonadotrophins then stimulate the gonads to release testosterone or oestrogen

Pulsatile

Mini puberty in the late foetal and early infant (first 6 months) stage where the HPG axis is active, and there is oestradiol and testosterone production in girls and boys respectively. This is for the early maturation of the organs. HPG axis is not active during childhood; GnRH secretion increases in noctural pulsatility during puberty; and as puberty is established, pulsatility continues during day and night

Question 10

Why is mini puberty important? What happens if a person does not undergo mini puberty?

Answer 10

Misses out some key development (espcially in boys); e.g. if a boy does not undergo mini pubterty, they often have Kallmann’s syndrome = lack GnRH, maldescended testes, cryptorchidism (testes fail to descend from the abdomen to the scrotum)

Question 11

In which sexes are delayed and precocious puberty more common in?

Answer 11

Delayed = boys

Early / precocious = girls

Question 12

When does menarche occur?

Is it common for periods to be irregular at the start? And why?

What’s the difference between primary and secondary amenorrhoea?

Answer 12

Menarche = onset about 2.3 years after thelarche, average age = 12.7 years (ranges from 10.7 - 16.1 years)

Yes, especially for the first 18 months - often because they are regarded as being anovulatory (no oocyte released)

Amenorrhoea = no periods for 3-6 months

Primary = never had periods (so a girl not having reached menarche after 16 years will be described as having primary amenorrhoea)

Secondary = used to have periods, but have now stopped

Question 13

What is the average length of the menstrual cycle in women?

How is amenorrhea signified in clinic?

What is meant by the term oligomennorhoea?

Answer 13

24-35 days

Absence of periods for more than 3-6 months; or less than 3 periods a year

Average length of the menstrual cycle is over 35 days; or 4-9 cycles per year

Question 14

What are the 3 different phases of the menstrual cycle?

How do the hormone levels change across the follicular stage of the cycle and what physiological changes occur due to this?

Hints:

1. Which hormone levels rise and what does that stimulate?
2. What hormones are released by the growing follicles and what are their effects?
3. Which hormone level drops and how does this affect the follicles?
4. What is the name given to the follicle that continues to grow, and how does the feedback mechanism change according to the production of oestradiol?

Answer 14

3 phases: Follicular phase, Ovulation phase, Luteal phase

Follicular phase: 1. FSH levels rise, which stimulates 2-3 follicles start to grow

2. As the follicles begin to grow, they begin to produce the hormones oestradiol and inhibin B; both of which provide negative feedback to the hypothalamus and pituitary gland so there is less FSH production
3. The reduction in FSH causes the death of the smaller / less developed follicles as they are FSH dependent - so there is atresia of the smaller follicles (larger follicles are less FSH dependent and so survive)
4. The large follicle survives - known as the dominant Graafian follicle, it continues to grow and so produce estradiol; low estradiol production = negative feedback on the hypothalamus and pituitary, but high estradiol levels causes a switch to positive feedback on the hypothalamus and pituitary

Question 15

How do the hormone levels change across the ovulation stage of the cycle and what physiological changes occur due to this?

1. In which hormone levels is there a surge? What is this surge caused by?
2. What action does this surge cause?

How can women use kits to measure exactly when they ovulate?

Answer 15

Ovulation: 1. There is then an LH surge due to the switch in feedback mechanisms by the ostradiol, so the positive feedback causes the LH surge = induces ovulation (typically day 14)

2. Release of egg from follicle - bgeins to travel down the fallopian tube, and may be fertilised by a sperm

Kits can measure LH levels in the urine, when the LH levels are at their peak in the urine, that indicated the ovulation stage

Question 16

How do the hormone levels change across the luteal phase of the cycle and what physiological changes occur due to this?

1. What does the rest of the follicle form? What hormone(s) does this secrete?
2. What actions take place due to the secretion of the hormone(s)?

Answer 16

Luteal phase: 1. The rest of the follicle forms the corpus luteum = secretes progesterone and oestradiol throughout the second half of the cycle

1. The progesterone and oestradiol are important for the development of the endometrium of the uterus; mid-luteal phase = peak progesterone levels; afterwards progesterone levels decline, drop in progesterone levels trigger bleeding of the menstrual cycle

Question 17

How to test for infertility in the menstrual cycle?

Answer 17

If mid-luteal progesterone levels are high, it suggests ovulation has taken palce (as the corpus luteum is able to secrete progesterone)

Question 18

What are the 3 phases of the menstrual cycle in accordance to the endometrium lining, and what occurs in each of these phases??

Answer 18

Menstrual phase (days 1 - 5) = break down of endometrium lining, bleeding

Proliferative phase (days 6 - 14) - as oestradiol levels increase, it causes proliferation and thickening of the endometrium

Secretory phase (days 15 - 28, same as luteal phase) - progesterone based, so the endometrium remains thickened and is full of blood vessels = receptive to an embryo

Question 19

What happens if there is successful implantation of an embryo? What hormone is secreted and how does that affect the corpus luteum?

Which hormone is measured in a pregnancy test?

Answer 19

The embryo will start secreting beta-hCG (human chorionic gonadotropin), which is similar to other hormones, such as LH and so can also activate LH receptors - therefore, if pregnancy takes place, B-hCG continues to support the corpus luteum as the corpus luteum needs LH stimulation to survive, so the B-hCG acts on the LH receptors on the corpus luteum. Therefore there is continual production of progesterone from the corpus luteum

beta-hCG

Question 20

Why is it important GnRH is released in a pulsatile manner from the hypothalamus?

How can the knowledge of the pulsatile release of GnRH be used clinically?

How is GnRH release during the menstrual cycle tested / measured clinically? What do the results show of the changes in pulsatility of GnRH across the follicular, ovulation and luteal phases?

Answer 20

So there is continuous stimulation of the pituitary, if GnRH is released in a non-pulsatile manner, there is inhibition of the pituitary, so a decrease in LH / FSH which results in low levels of sex hormones

e.g. for prostate cancer, reduction in testosterone production is achieved by delivering high doses of continuous GnRH

LH levels tested instead of GnRH (as GnRH is not released into the systemic blood circulation, so too low to detect in the systemic blood) - LH peak levels detected every 90 mins so GnRH pulse is released every 90 mins

Pulses increase in frequency whilst approaching ovulation, then LH surge. Luteal phase = lower frequency of pulses of GnRH (due to the negative affect of the progesterone on the hypothelamus and pituitary)

?

Question 21

What is hypogonadism? How is this picked up clinically?

What are the 2 types of hypogonadism and what are the possible causes of hypogonasism?

What can be measured in blood to differentiate between the 2 types of hypogonadism?

Answer 21

Underactive / reduced gonadal function; low oestrogen / testosterone levels in women and men respectively

1. Primary hypogonadism = something affects the gonads directly e.g. trauma to the testes / ovaries, which reduces negative feedback on the hypothalamus and pituitary so high levels of LH and FSH are found in the blood
2. Secondary hypogonadism = something affects the hypothalamus or pituitary gland so there is little / no LH or FSH production, and it does not increase due to low sex hormone levels, so ultimately there is an issue with LH/FSH release e.g. pituitary tumour or high prolactin levels

Both types of hypogonadism as indicated by low oestrogen / testosterone levels, however, if accompanied by high LH / FSH levels, it indicates primary hypogonadism, or if accompanied by low LH/FSH levels, indicates secondary hypogonadism

Question 22

Menopause is what type of hypogonadism?

What are the hormone level s clinically during menopause?

Increase in LH is associated with what, and increase in FSH is associated with what?

What are the syptoms of menopause?

When is menopause diagnosed?

Treatments for menopause?

Answer 22

Primary = reduced function of ovaries = reduced oestradiol = increase in LH / FSH

High LH/FSH; low inhibin

High FSH = lack of gametes; High LH = lack of sex steroids

Predominantly symptoms of low oestradiol: Hot flushes, skin dryness, hair thinning, mood disturbance, osteoporosis (due to decrease in osteoblast stimulation), sexual dysfunction, weight gain, amenorrhoea, climacteric = irregular periods til they eventually stop

When the periods have stopped for over a year

Most symptoms due to low oestrogen = low doses of oestrogen given (HRT - hormone replacement therapy)

Question 23

What are some symptoms of hypogonadism?

How can questions regarding these symptoms be asked clinically?

Answer 23

Decreased libido, loss of body hair, decreased muscle mass / muscle strength, decreased mood, sleep disturbances, erectile dysfunction etc.

Do you shave as often as you normally do?

Are your energy levels lower?

Do you have erectile dysfunction?

Have you noticed changes in body composition / muscle mass?

Are you taking any steroids? / Are you on any other drugs?

Are you depressed? Anxious?

Are you stressed?

What is your alcohol intake like?

Any trauma to the testes / head / anywhere really?

Have you broken any bones / fractures? = osteoporosis symptoms due to low GnRH?

Any headaches?

Any bitemporal hemianopia? / loss in peripheral vision?

Question 24

What investigations can be performed to diagnose hypogonadism and find the cause?

Answer 24

Blood tests - measure LH / FSH / testosterone / oestrogen levels

Physical examination e.g. if they’re a dude, check if they have undergone minipuberty (Kallmann’s Syndrome / XXY chromosomes)

Testicular volume

Measure prolactin levels in the blood

Scans to look for tumour e.g. prolactinoma

Question 25

What are the risks with just giving oestrogen HRT and why?

What can make the HRT better?

Answer 25

Oestrogen stimulates endometrium proliferation, but some women may already have their endometrium intact, so if the endometrium stimulation goes unopposed, there are risks of endometrium hyperplasia (abnormally thick uterine lining) or cancer

HRT includes progesterone as well as the oestrogen - as the progesterone prevents further thickening of the endometrium

Question 26

What is the concept of the ovarian reserve?

What are ‘ovarian reserve’ markers? What is the most common marker? How does it detect the size of the ovarian reserve?

What is the avergae age of menopause?

At what age is premature menopause (POI - premature ovarian insufficiency) diagnosed?

How is POI diagnosed? What is the prognosis for POI?

Causes of POI?

Answer 26

The gradual decrease from the total number of egg cells present from foetal life, until menopause where they eventually run out (fall v. low) is the concept of the ovarian reserve - so the ovarian reserve refers to the woman’s remaining egg supply that can produce babies

Hormone to ascertain the size of the ovarian reserve - AMH (anti-mullerian hormone) = released from sertoli cells in the ovaries, and peaks in early adult life, and goes v. low at menopause

45-55yrs (generally)

Before 40 years

High FSH levels, low oestradiol levels on 2 different occations 4 weeks apart. Prognosis different to normal menopause, conception can occur in 20%

Coeliac disease, autoimmune conditions (attack the ovaries/ thyroid etc.), genetic syndromes (e.g. Turner’s), cancer treatments, etc.

Question 27

Spermatogenesis is more or less consistent throughout the male lifespan. So is there a male equivalent to menopause, - andropause? What may cause it?

Answer 27

Yes, kind of - free testosterone levels fall more steeply

Question 28

What is it called when the fall in free testosterone levels are associated with symptoms?

What is meant by the term ‘free testosterone’? What is all the other testosterone bound to?

Why do free testosterone levels decrease with age?

Answer 28

Late onset hypogonadism

60% of testosterone is bound strongly to SHBG (sex hormone binding globulin) = inactive (cannot be released into the tissues); 38% bound to albumin, bound less strongly = bioactive, it has potential for release into tissues; therefore only 2% of testosterone is not bound to anything = ‘free’ = active

Total testosterone remains unchanged, but SHBG increases so more testosterone is bound to SHBG making it inactive = reduction in free / active testosterone

Question 29

What rhythm / pattern does testosterone levels follow?

What else can affect testosterone levels?

How can late onset hypogonadism in men be diagnosed?

Answer 29

Diurnal rhythm - high in the morning, gradually falls throughout the day

Sugar (glucose) decreases testosterone levels

Measure testosterone levels before 11am, ideally when fasting, on 2 separate occasions to confirm free testosterone levels have reduced

Question 30

What are some symptoms of testosterone deficiency?

Answer 30

Sexual dysfunction (reduced libido), erectile dysfunction (loss of early morning erections), reduced hair growth (reduction in frequency of shaving), fatigue, mood disturbance, change in body composition (increase in fat, reduction in muscle mass, gynaecosmatia - breast enlargement in men), reduction in spermatogenesis, reduction in bone health due to less testosterone conversion to oestrogen

Question 31

What are the 2 main enzymes found in local tissues that affect / change testosterone?

What can increase the function of aromatase?

Answer 31

1. 5alpha-reductase - found in the testes, prostate glabd and scalp, it metabolises testosterone into dihydrotestosterone (DHT), more potent version of testosterone - important for prostrate growth and male pattern baldness
2. Aromatase - found in adipose tissue, adrenal glands, ovaries (granulosa cells), testes (sertoli cells), brain, bone, skin, it metabolises testosterone to oestradiol, which is important for bone density

Aromatase is stimulated by - weight gain, age, obesity, gonadotrophins, alcohol

Question 32

How can weight gain as a stimulant for increased aromatase activity be used clinically?

Answer 32

Weight loss can be used as a treatment to increase testosterone levels

Increased oestrogen in breast cancer can cause increased proliferation of breat tissue, so aromatase inhibitors can be given to reduce oestradiol production as a treatment for cancer and to reduce re-occurance

Question 33

How can the knowledge of 5alpha-reductase be used to treat prostrate cancer?

Answer 33

DHT = responsible for prostrate growth, so reduce DHT production by inhibiting 5alpha-reductase, using a 5alpha-reductase inhibitor

Question 34

DHT affects which secondary sexual characteristics more, and Testosterone affects which secondary characteristics more?

Draw out the male reproductive axis:

Answer 34

DHT = affects prostrate and facial hair growth more so

T = affects / regulates erectile function and libido