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Y2 LCRS 1 - Endocrinology > Endocrine Infertility > Flashcards

Endocrine Infertility Flashcards

1
Q

Describe the hypothalamo-pituitary-testicular axis.

A
  • GnRH released from hypothalamus in a pulsatile fashion
  • This triggers FSH and LH release from anterior pituitary
  • FSH stimulates the testes to produce inhibin
  • LH stimulates the testes to produce testosterone
  • Negative feedback
    • Inhibin:
      • Inhibits FSH secretion from anterior pituitary
      • Inhibits GnRH secretion from hypothalamus
    • Testosterone
      • Inhibits LH secretion from anterior pituitary
      • Inhibits GnRH secretion from hypothalamus
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2
Q

What are the three phases of the menstrual cycle?

A

28 day cycle (on average)

  1. Follicular phase
  2. Ovulation
  3. Luteal phase
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3
Q

Describe the hypothalamio-pituitary ovarian axis.

A
  • GnRH released from hypothalamus in a pulsatile fashion
  • This triggers FSH and LH release from anterior pituitary
  • FSH and LH stimulate the ovaries to produce oestradiol (oestrogen), progesterone and inhibin
  • Negative feedback
    • Ostradiol, progesterone and inhibin
      • Inhibits FSH and LH secretion from anterior pituitary
      • Inhibits GnRH secretion from hypothalamus
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4
Q

What happens during the follicular phase?

A
  • At the beginning of the menstrual cycle, oestrogen and progesterone levels are low
  • So there is little -ve feedback on hypothalamus and pituitary
  • This leads to an increase in pulsatile release of GnRH and therefore release of FSH and LH
  • FSH and LH stimulate the ovaries to produce oestradiol
  • FSH also stimulates the ovaries to produce inhibin
  • Negative feedback:
    • High levels of oestradiol inhibit FSH and LH release from anterior pituitary
    • Inhibin inhibts FSH release
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5
Q

What happens during ovulation?

A

Extremely high concentrations of oestradiol (for long enough) results in:

  • negative feedback → positive feedback
  • This positive feedback triggers an LH surge
  • LH surge → ovulation

NOTE: No FSH surge due to negative feedback by inhibin

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6
Q

What happens during the luteal phase?

A
  • Ovulation has already taken place
  • If implantation does NOT occur → endometrium is shed (menstruation)
  • If implantation DOES occur → pregnancy

NOTE: Implantation = the adherence of a fertilised egg to the uterus lining so that the egg may have a suitable environment for growth and development

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7
Q

Define infertility.

A

Inability to conceive after 1 year of regular unprotected sex

NOTE:

  • 1 in every 7 couples
  • Caused by abnormalities in:
    • males (30%)
    • females (45%)
    • unknown (25%)
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8
Q

State the two main causes of infertility.

A

Primary gonadal failure

Hypothalamic/pituitary disease (i.e. tertiary/secondary failure)

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9
Q

What is primary gonadal failure and what effects does it have on the hypothalamo-pituitary-gonadal (HPG) axis?

A
  • It is a problem with the gonads (i.e. testes/ovaries)
  • The testes/ovaries fail to produce enough testosterone/oestradiol
  • Therefore, there is no negative feedback on the HPG axis → high GnRH, FSH and LH
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10
Q

How does hypothalamic and pituitary disease affect the HPG axis?

A

Hypothalamic disease → low GnRH → low FSH and LH → low testosterone/oestradiol (tertiary hypogonadism)

Pituitary disease → low FSH and LH → low testosterone/oestradiol (secondary hypogonadism)

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11
Q

State some of the clinical features of male hypogonadism.

A
  • Loss of libido = sexual interest / desire
  • Impotence
  • Small testes
  • Decreased muscle bulk
  • Osteoporosis

NOTE: Testosterone stimulates protein synthesis (anabolic effect) → muscle and bone growth

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12
Q

State some causes of male hypogonadism.

A
  • Hypothalamic-pituitary disease
    • Hypopituitarism
    • Kallmans syndrome (characterised by anosmia = absent sense of smell & low GnRH)
    • Illness / underweight
  • Primary gonadal disease (i.e. failure of testes to produce sufficient testosterone)
    • Congenital: Klinefelters syndrome (XXY)
    • Acquired: testicular torsion, chemotherapy
      • Testicular torsion = twisting of spermatic cord which supplies blood to the testes, leading to ischaemia
  • Hyperprolactinaemia (this inhibits pulsatile release of GnRH which is essential for stimulating LH and FSH release)
  • Androgen receptor deficiency (on end/target organs)
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13
Q

What are the main investigations for male hypogonadism?

A
  • LH, FSH and testosterone levels
    • If all are low → pituitary MRI (to check if there is a problem with the pituitary gland)
  • Prolactin levels (to check for hyperprolactinaemia)
  • Sperm count
    • Azoospermia – absence of sperm in ejaculate
    • Oligospermia – reduced number of sperm in ejaculate
  • Chromosomal analysis (check for Klinefelter’s: XXY)
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14
Q

What is given to all patients with male hypogonadism?

A

Testosterone to increase muscle bulk and protect against osteoporosis

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15
Q

How do you restore fertility in someone with male hypogonadism?

A

Subcutaneous gonadotrophin (i.e. FSH and LH) injections → stimulates testosterone release

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16
Q

What is the treatment for hyperprolactinaemia?

A

Dopamine agonists

  • These are essentially D2 receptor agonists to stimulate dopamine release from the hypothalamus
  • Dopamine inhibts prolactin release from anterior pitutiary
  • Increased dopamine release → decrease prolactin release → decreased inhibition of GnRH pulsatility (pulsatile release)
17
Q

State some endogenous sites of production of androgens.

A
  • Interstitial Leydig cells of the testes
    • Interstial - i.e. present in the interstitial fluid between the seminiferous tubules
  • Adrenal cortex (males and females)
  • Ovaries
  • Placenta
  • Tumours (of ovaries or adrenal cortex)
18
Q

What are the main actions of testosterone?

A
  • Development of the male genital tract
  • Maintains fertility in adulthood
  • Control of secondary sexual characteristics
  • Anabolic effects (muscle, bone)
19
Q

How is testosterone found in the circulation?

A

Heavily plasma protein bound - 98%

20
Q

State two products that testosterone can be converted to and the enzymes responsible for these conversions and the receptors via which testosterone acts.

A

These conversions are tissue-specific

  • Testosterone → dihydrotestosterone (DHT)
    • Enzyme: 5α-reductase
    • Receptor: androgen receptor (AR)
  • Testosterone → 17β-Oestradiol (E2)
    • Enzyme: aromatase
    • Receptor: oestrogen receptor (ER)
    • ERs found in brain and adipose tissue
      • Brain - behavooural effects
      • Adipose tissue - metabolic actions on lipids
21
Q

What type of receptors does DHT and E2 act on?

A

Nuclear receptors (i.e. present in the nuclear)

22
Q

What are the clinical uses of testosterone in adulthood?

A
  • Lean body mass (fat-free body mass)
  • Muscle size and strength
  • Bone formation and bone mass (in young men)
  • Libido and potency

Testosterone alone does not restore fertility

  • Infertility requires treatment with gonadotrophins (FSH and LH) to restore normal spermatogenesis
    • FSH and LH stimulates spermatogenesis and testosterone production
    • Testosterone regulates spermatogenesis and initiates the functional responses required to support spermatogenesis

NOTE: Potency = ability to get or keep an erection which allows the male to have sex

23
Q

What is amenorrhoea?

A

The absence of periods

24
Q

What is the difference between primary and secondary amenorrhoea?

A

Primary Amenorrhoea = failure to develop spontaneous menstruationby the age of 16 years

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

25
Q

What is oligomenorrhoea?

A

Irregular long cycles

  • The normal cycle ranges from 21-35 days
  • If the cycle is longer then 35 days, then periods are infrequent
  • This is oligomenorrhoea (infrequent periods)
26
Q

List some causes of amenorrhoea.

A

Pregnancy

  • High oestrogen and progesterone inhibits further menstruation (suppresses FSH/LH and GnRH)

Lactation

  • High prolactin stimulates milk production
  • Prolactin suppresses GnRH pulsatility (pulsatile release)

Ovarian failure:

  • Premature ovarian failure (early menopause becuase your ovaries stop working properly)
  • Ovariectomy / chemotherapy
  • Ovarian dysgenesis (Turners 45 XO) – lacking one chromosome

Gonadotrophin failure:

  • Hypothalamic/pituitary disease
  • Kallmann’s syndrome (anosmia, Low GnRH)
  • Low BMI
  • Post pill amenorrhoea
    • When you stop taking the pill, it can take some time for your regular ovulation and menstruation to return
      • Contraceptive pill - oestrogen only or oestrogen and progesterone
      • They suppress GnRH, FSH and LH
      • So it can take some time once you stop taking the pill to return to the normal production of these hormones

Hyperprolactinaemia

Androgen excess: gonadal tumour

  • Excess androgen production suppresses GnRH, FSH and LH → inhibits further menstruation
27
Q

State some features of Turner’s syndrome.

A
  • 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 (abnormal ovarian development)

1:5000 live female births

28
Q

Why does low BMI cause amenorrhoea?

A
  • Leptin released by adipocytes
  • Low BMI = low leptin
  • Lack of leptin acting on the brain results in the brain shutting down the reproductive axis
  • This is because lots of energy is required to reproduce
    • Fat is an energy store
29
Q

State some investigations for amenorrhoea.

A
  • Pregnancy test
  • LH, FSH, oestradiol
  • Day 21 progesterone (should be at its peak)
  • Prolactin, thyroid function tests
    • Hyperthyroidism → low BMI → amenorrhoea
  • Androgens (testosterone, androstenedione, DHEAS)
    • DHEA sulphate - steroid hormone produced in adrenal cortex, exists in conjugated form
    • Androstenedione - produced in adrenal cortex and gonads
    • Androstenedione and DHEA are precursors to testosterone
  • Chromosomal analysis (Turners 45 XO)
  • Ultrasound scan ovaries / uterus
30
Q

How can amenorrhoea be treated?

A

Treat the cause (e.g. low weight)

Primary ovarian failure (infertile) – HRT

Hypothalamic/pituitary disease

  • HRT for oestrogen replacement
  • Fertility: Gonadotrophins (LH & FSH)
    • This usually part of IVF treatment
    • In IVF, gonadotrophins are given to stimulate development of multiple eggs to increase chance of successful pregancy

Explanation:

  • Essentially if you have amenorrhoea, you are usually lacking oestrogen
  • Lack of oestrogen makes you infertile
  • However, oestrogen has other important functions (e.g. anabolic effect on bone, effects on lipid metabolism)
  • Therefore, the first line of treatment should be oestrogen HRT but this alone is not enough to make you fertile
  • Therfore you need to give FSH and LH - need to give HRT if you have a hypothalamic/pituitary disease
31
Q

What is PCOS?

A

PCOS = Polycystic ovarian syndrome

  • Syndrome = a group of symptoms which consistently occur together
  • The main feature of PCOS is excess androgens
  • This is likely to have multiple underlying pathophysiological mechanisms
    • Increased pulse frequency of GnRH → LH hypersecretion → increased androgen production within ovaries
    • Metabolic disturbance → insulin resistance → compensatory hyperinsulaemia
      • ​Insulin increases the ovarian response to LH so further increases androgen production
  • Incidence: 1 in 12 women of reproductive age
  • Associated with insulin resistance (leads to diabetes)
    • Leads to increased cardiovascular risk
32
Q

What are the criteria for diagnosing PCOS?

A

They must have at least 2 of the following:

  • Polycystic ovaries on ultrasound scan
    • These ‘cysts’ are actually immature follicles which have not been able to develop properly due to the ovaries not functioning as normal
  • Clinical/biochemical signs of androgen excess
  • Oligoovulation/anovulation
    • Anovulation → infertility
    • Anovulation due to follicles not being able to mature
33
Q

What are the clinical features of PCOS?

A

Hirsuitism (due to androgen excess)

Menstrual irregularities (due to hormonal imbalance - androgen and LH excess)

Increased BMI (due to insulin resistance)

34
Q

Describe the treatment for PCOS.

A

Metformin

  • Makes tissues more sensitive to insulin
  • This decresases insulin levels which improves fertility
    • Insulin resistance causes compensatory hyperinsulaemia
    • Hyperinsulaemia can impact ovarian function and lead to problems with ovulation

Clomifene

  • Is anti-oestrogenic in the hypothalamo-pituitary axis
  • Bind to oestrogen receptors in the hypothalamus thereby blocking the normal negative feedback by oestrogen binding
  • This results in an increase in the secretion of GnRH and gonadotrophins (FSH and LH)

Gonadotrophin therapy as part of IVF treatment

35
Q

What hypothalamic hormone has a stimulatory effect on prolactin release?

A

Thyrotrophin releasing hormone (TRH)

36
Q

What effect does hyperprolactinaemia have on the HPG axis?

A

It reduces GnRH pulsatility

  • GnRh released at constant low rate - no pulses where there is suddenly more release
  • The pulse frequency affects the release of FSH or LH so is very important in regulating gonodotroph release

It will inhibit LH actions on the ovaries and testes

  • Reduced gonadal function
37
Q

State some causes of hyperprolactinaemia.

A

Dopamine antagonist drugs

  • Anti-emetics (metoclopramide)
    • Drug used to treat vomiting and nausea
    • Dopamine receptors in vomiting centre - cause vomiting/nausea when stimulated
  • Anti-psychotics (phenothiazines)
    • Psychosis can be caused by problems with the dopamine system in certain parts of the brain
    • e.g. schizophrenia patients have an overactive dopamine system
  • Dopaminergic neurones and dopamine receptors present throughout brain, including the parts involved in causing vomiting (vomiting centre) and psychosis

Prolactinoma (pituitary adenoma of lactotrophs)

Stalk compression due to pituitary adenoma

  • This prevents the dopamine from the hypothalamus from getting to and exerting its inhibitory effect on the lactotrophs (in the anterior pituitary)
  • Lack of inhibition → increased prolactin production

Hypothyroidism

  • Low levels of thyroid hormones means lack of suppression of TRH production
  • More TRH to overcome dopamine inhibition and stimulate prolactin production

Oestrogens (oral contraceptive pill - OCP)

  • Oestrogen - stimulates prolactin production and secretion (therefore involved in regulation of prolactin)

PCOS

  • Results in high levels of androgens
  • Androgens can be converted to oestrogen so also high levels of oestrogen

Pregnancy and lactation

  • Levels of prolactin start increasing during pregnancy to prepare for lactation

Idiopathic (unknown cause)

38
Q

What are the clinical features of hyperprolactinaemia?

A
  • Galactorrhoea
  • Reduced GnRH secretion / LH action → hypogonadism (reduced testosterone/oestrogen)
  • Prolactinoma
    • Headache - increased pressure (around pituitary gland)
    • Visual field defect - compression of optic chiasm just above pituitary gland
39
Q

How is hyperprolactinaemia treated?

A

Treat the cause of hyperprolactinaemia

  • By treating this and decreasing prolactin levels, this will increase fertility
  • This is a better option than just giving the patient fertility drugs (e.g. hormone replacement)

Dopamine agonist - e.g:

  • Bromocriptine
  • Cabergoline

For a prolactinoma:

  • Dopamine agonist therapy
  • Pituitary surgery rarely needed

Y2 LCRS 1 - Endocrinology (20 decks)

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