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Endocrinology year 2 > Endocrine infertility > Flashcards

Endocrine infertility Flashcards

1
Q

Outline the male hypothalamus-pituitutary-gonadal axis

A

Hypothalamus- pulsatile release of GnRH (hourly)
Stimulaties gonadotrophes of anterior pituitary to release LH and FSH
LH- Leydig cells to produce testosterone
FSH- Sertoli cells (seminiferous tubules)- to make sperm and inhibin A and B
Testosterone is needed to support spermatogenesis in the Sertoli cells

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2
Q

Summarise the regulation of the male HPG axis

A

Testosterone exerts a negative feedback loop on the hypothalamus and APG (LH)
Inhibin is produced by Sertoli cells that also exerts a negative feedback loop (FSH)

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3
Q

Summarise the ovarian cycle in females

A

28 day menstrual cycle:

follicular phase

ovulation

Luteal phase

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4
Q

Summarise the female HPG axis

A

GnRH released in pulses each hour from hypothalamus
GnRH causes pulsatile LH/FSH release from the APG
FSH causes follicles to start maturing
Maturing follicles produce oestrogen which has a negative feedback on the APG and hypothalamus
High levels of oestrogen activated positive feedback receptors in the hypothalamus to cause an LH surge
Corpus luteum secretes progesterone to negatively feedback FSH/LH, and if egg not fertilised then will reduce to allow new cycle

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5
Q

Describe the role of LH in the ovaries

A

Oestradiol and progesterone production
LH acts on the thecal cells to stimulate them to make androgens.
These androgens then act on the granulosa cells (which under control from FSH) synthesise aromatase to produce oestrogens (mostly 17b-oestradiol).
Stimulating growth of the antral follicles.

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6
Q

Describe the role of FSH in the ovaries

A

Follicular development and inhibin production
As oestrogen has a negative feedback effect on the FHS- the antral follicles still dependent on FSH for growth are arrested- atresia.
Graafian follicle left behind (largest follicle)- responds to its own oestrogen released- this increases oestrogen concentration massively enough to exert a positive feedback effect on the hypothalamus to stimulate the LH surge necessary for ovulation.

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7
Q

What are the two results of the luteal phase

A

In the luteal phase, if implantation does not occur, the endometrium is shed (menstruation) but if implantation does occur, pregnancy.

Need to shed endometrium- to reduce risk of endometrial cancer.

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8
Q

Define infertility

A

Infertility: inability to conceive after 1 year of regular unprotected sex.
May be increased to 2 (financial reasons- as IVF is expensive).

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9
Q

Describe the epidemiology of infertility

A

1:6 couples

Caused by abnormalities 
in males (30%)
or females (45%)
or unknown (25%)
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10
Q

Describe the key features of primary gonadal failure

A

Primary gonadal failure: problems with testes/ovaries leading to low testosterone/oestradiol; high GnRH, LH and FSH as no negative feedback

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11
Q

Describe secondary gonadal failure

A

Secondary (hypo/pit) disease: problems with hypothalamus/pituitary gland leading to low LH/FSH and hence low testosterone/oestradiol
Don’t measure GnRH- as we can’t access the hypothalamus-portal network of blood vessels- but it will be low.

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12
Q

What are the clinical features of male hypogonadism

A 
Loss of libido = sexual interest / desire
Impotence 
Small testes
Decrease muscle bulk
osteoporosis
Essentially, features of no testosterone
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13
Q

Describe the hypothalamus-pituitaury causes of male hypogonadism

A 
Hypopituitarism- tumour, damage or inflammation 
Kallmans syndrome (anosmia & low GnRH, and failure to go through puberty)- occur together as olfactory neurones and GnRH neurones migrate together in embryogenesis- may fail to occur
Idiopathic hypogonadotrophic hypogonadism- low GnRH without loss of smell- congenital abnormality. 
Illness / underweight - leptin permissive on GnRH secretion- don't want to have a baby when underweight- body assumes there aren't enough resources.
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14
Q

Describe primary gonadal disease as a cause of male hypogonadism

A

Congenital: Klinefelters syndrome (XXY) - commonest cause
Acquired: Testicular torsion, Chemotherapy

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15
Q

Describe the features of Klinefelters syndrome

A 
Small, firm testes
Low IQ
Gynaecomastia
Tall height (start of puberty normal)
Lower testosterone levels
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16
Q

Describe some other causes of male hypogonadism

A

Hyperprolactinaemia- inhibitory effect on gonadotrophin release.

Androgen receptor deficiency

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17
Q

What are the key investigations for male hypogonadism

A

LH, FSH, testosterone
If all low&raquo_space; MRI pituitary (to check for damage to the pituitary)

Prolactin

Sperm count
Azoospermia = absence of sperm in ejaculate
Oligospermia = reduced numbers of sperm in ejaculate

Chromosomal analysis (Klinefelters XXY)

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18
Q

Describe the two factors we check for in sperm samples

A

Sperm count- at least 6 million

Abnormal sperm- so look at sperm motility.

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19
Q

Summarise the treatment for male hypogonadism

A

§ HRT – replace testosterone for ALL patients (usually once every 3 months).

§ For fertility – testosterone isn’t enough, need SC gonadotrophins (LH&FSH).

§ Hyperprolactinaemia – dopamine agonist to inhibit prolactin.

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20
Q

State the endogenous sites for the production of androgens

A
  1. interstitial Leydig cells of the testes
  2. adrenal cortex (males and females)
  3. ovaries
  4. placenta
  5. tumours (rare- usually really high levels)
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21
Q

State the main actions of testosterone in the body

A
  1. development of the male genital tract
  2. Maintains fertility in adulthood
  3. Control of secondary sexual characteristics
  4. Anabolic effects (muscle, bone)
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22
Q

What is testosterone bound to in the blood

A 
Circulating testosterone (98% protein bound)- sex hormone binding globulin
note- binds to androgen binding globulin in the seminiferous tubules.
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23
Q

Describe the tissue-specific processing of testosterone

A

Brain and adipose tissue: testosterone will be converted to 17b-oestradiol by aromatase. This acts via the oestrogen receptor to stimulate water reabsorption in the epididymis and development of male behaviours. Why obese people may have problems with fertility.

5a-reducatase can convert it to DHT- act via the androgen receptor. DHT is more potent than testosterone.

MECHANISM OF ACTION OF DHT / E2 is via nuclear receptors

24
Q

Explain the clinical uses of testosterone replacement therapy

A 
Testosterone in adulthood will increase
lean body mass
muscle size and strength
bone formation and bone mass (in young men)
libido and potency

It will not restore fertility, which requires treatment with gonadotrophins to restore normal spermatogenesis.

25
Q

When is testosterone replacement therapy indicated.

A

Replacement therapy to treat:
Primary testicular failure/primary hypogonadism (disorder intrinsic to testes)
Hypogonadotropic or secondary hypogonadism

26
Q

Summarise the treatment for hyperprolactinaemia

A

Dopamine agonists – bromocriptine and cabergoline

Pituitary surgery (though this is rarely used because medicine normally works well)

27
Q

Define amenorrhea

A

Amenorrhoea = absence of periods

Primary amenorrhoea = failure to begin spontaneous menstruation by age 16 years

Secondary amenorrhoea = absence of menstruation for 3 months in a woman who has previously had cycles

History essential here- as it’s hard to determine from hormone levels- as they are extremely pulsatile.

28
Q

Define oligomenorrhoea

A

Oligomenorrhoea = irregular long cycles

29
Q

Describe some physiological causes of amenorrhea

A

Pregnancy ! / Lactation

Pregnancy- oestrogen and progestogen high- inhibit lH and FSH release- no cycle

Lactation- prolactin released- inhibitory effect on gonadotrophin release.

30
Q

Describe some causes of ovarian failure which can lead to amenorrhea

A 
premature ovarian insufficiency. 
Ovariectomy / chemotherapy
ovarian dysgenesis (Turners 45 XO) – lacking one chromosome
31
Q

Describe premature ovarian insufficiency

A

Normal menopause occurs between 45 and 55 (average is 51)
May be due to autoimmune damage
All the oocytes have apoptosed.

Oestrogen low
LH and FSH- high.

32
Q

Describe the key features of Turners syndrome

A 
12 year old girl
short stature
cubitus valgus (wide carrying angle)- (forearm is angled away from the body to a greater degree than normal when fully extended)
gonadal dysgenesis
1:5000 live F births-
33
Q

Describe how gonadotrophin failure can lead to amenorrhea

A

Gonadotrophin failure:
Hypo / pit disease
Kallmann’s syndrome (anosmia, Low GnRH)
Low BMI - low leptin shuts off the reproductive system
Post pill amenorrhoea- contraceptive pill (high oestrogen and progesterone)- will shut off hypothalamus- can shut off completely if used for prolonged periods of time- wean off every 4 years.

34
Q

Describe some other causes of amenorrhea

A

Hyperprolactinaemia

Androgen excess: gonadal tumour

35
Q

Describe the different investigations for amenorrhea

A

Pregnancy test

LH, FSH, oestradiol (need to be very low to be of use- due to pulsatile nature).

Day 21 progesterone (should be raised if ovulation is occurring. This assumes a 28 day cycle. Thus you really need to get a sample 7 days before the next period, and one way to do this is to take a sample every 3 days from day 21, so that one catches the peak in progesterone in someone with irregular periods.

Prolactin, thyroid function tests (primary hypothyroidism0 low thyroxine leads to reduced negative feedback causing a rise in TRH increasing prolactin release).

Androgens (testosterone, androstenedione, DHEAS)

Chromosomal analysis (Turners 45 XO)

Ultrasound scan ovaries / uterus- look for PCOS

36
Q

What is important to remember about ovulation

A

May have a cycle- but no ovulation.

37
Q

Summarise the treatment of amenorrhoea

A

Treat the cause (eg low weight)

Primary ovarian failure – infertile, HRT

Hypothalamic / pituitary disease
HRT for oestrogen replacement
Fertility: Gonadotrophins (LH & FSH) – part of IVF treatment

38
Q

When is it essential to give HRT

A

Primary ovarian insufficiency- early menopause- not had their ‘dose’ of oestrogen needed for life- so won’t suffer from side effects of HRT
Can give it to patients post-menopause (normal)- but associated with side effects.

39
Q

Describe the epidemiology of PCOS

A

Incidence: 1 in 12 women of reproductive age

Associated with increased cardiovascular risk and insulin resistance (>diabetes) ? why

40
Q

Describe the Rotterdam criteria for PCOS

A

Need 2 of the following:

polycystic ovaries on USS
oligo- / anovulation
clinical / biochemical androgen excess

41
Q

Describe the clinical features of PCOS

A

Hirsuitism and acne (high levels of androgens).

Menstrual cycle disturbance (intermittent and variable in length)

Increased BMI

42
Q

Explain the hirsutism associated with PCOS

A

Increased secretion to thecal androgens (due to increased LH:FSH ratio). but insufficient aromatisation.
Thus there is an increase testosterone with a decrease in 17B-oestradiol.

43
Q

Describe the treatment of PCOS

A

METFORMIN – insulin sensitiser

CLOMIFENE – anti-oestrogenic effects in the hypothalamo-pituitary axis – binds to oestrogen receptors in the hypothalamus thereby blocking the negative feedback à increased GnRH and gonadotrophin secretion

GONADOTROPHIN THERAPY as part of IVF treatment

44
Q

What is recombinant LH

A

hCG

45
Q

In which sex is hyperprolactinaemia more common

A

Women

46
Q

Describe the hypothalamus-pituitary axis for prolactin

A

Major control is inhibitory- dopamine released from hypothalamus inhibits release of prolactin form the anterior pituitary.
The stimulatory control is via TRH release from the hypothalamus

47
Q

Describe the roles of prolactin

A

Lactation
Inhibits GnRH pulsatility (via caspeptin hormone)
Inhibits LH actions on ovary and testes- reduced testosterone production

48
Q

Describe the main causes of hyperprolactinaemia

A

Dopamine antagonist drugs
Anti-emetics (metoclopramide)
Anti-psychotics (phenothiazines)

Prolactinoma (becomes independent of dopamine inhibitory control)

Stalk compression due to pituitary adenoma (disconnects hypothalamus from pituitary- hence dopamine cannot exit its inhibitory control on prolactin.

49
Q

Describe the consequences of stalk compression on prolactin release

A

§ Stalk compression due to pituitary adenoma.

o Stalk compression may stop DA and TRH passing down and as there is a majority negative feedback, a compressed stalk allows an autonomous output to begin.

50
Q

Describe some other causes of hyperprolactinaemaia

A

PCOS

Hypothyroidism

Oestrogens (OCP)- contraceptive pill.

Pregnancy

Lactation

Idiopathic

51
Q

Describe the clinical features of hyperprolactinaemia

A

Galactorrhoea

Reduced GnRH secretion / LH action&raquo_space; hypogonadism

Prolactinoma
Headache
Visual field defect

52
Q

Describe the treatment for hyperprolactiaemia

A

Treat the cause – stop drugs- if you can’t can give HRT

Dopamine agonist
Bromocriptine

Cabergoline

Prolactinoma
Dopamine agonist therapy
Pituitary surgery rarely needed

53
Q

What is important to remember about LH and FSH levels in the context of hypothalamus/pituitary disease

A

Not necessarily low

Just not as high as they should be in the context of a low estradiol.

54
Q

If a patient has a micro adenoma (being treated with dopamine agonists) what advice should be given regarding breast feeding

A

a. She should go back onto dopamine agonists (cabergoline) after birth and not breast feed.
b. Her health is more important that natural breast feeding.

55
Q

Describe the hormone profile in pregnancy

A

a. High oestrogen, low FSH, low LH – pregnancy.

56
Q

After conception, should a patient with a micro adenoma be worried about a high prolactin

A

b. After she has conceived, she does not need to worry about high prolactin as at that point, it’s physiological – you would just be watching the size of the microadenoma in her pituitary though (she can stop the treatment if the adenoma is small enough).

Endocrinology year 2 (13 decks)

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