Ovulation Disorders and Male Hypogonadism Flashcards
Sequence of events in the hypothalamic pituitary gonadal axis?
GnRH released from the hypothalamus
This stimulates the anterior pituitary to produce LH and FSH, which have their own effects on target tissues
-ve or +ve feedback can occur, from steroid and peptide hormones (like oestrogen) at the gonads, affecting:
• GnRH release from the hypothalamus
• LH and FSH release from the anterior pituitary
Functions of oestrogenes?
Class of steroid hormones that control development and maintenance of female sexual characteristics
Where does glandular oestrogen synthesis occur?
Occurs in the granulosa and theca cells of the ovaries, as well as the corpus luteum
What happens when granulosa cells are stimulated by LH?
Produce pregnenolone
What happens to pregnenolone?
- Diffuses out of granulosa cells into adjacent theca cells which express enzymes (17,20-lyase and 17β-HSD)
- Enzymes mediate pregnenolone conversion to androstenedione (via DHEA)
- Most andosteedione returns to the granulosa cells and is converted to oestrone by aromatase
- Aromatase is then converted to oestradiol (by 17β-HSD)
How is expression of aromatase and 17β-HSD controlled?
By FSH stimulation
How does extraglandular synthesis of oestrogen occur?
Aromatase is expressed in non-gonadal sites and facilitates peripheral aromatisation of androgens to estrone, e.g: fat and bone
How is progesterone synthesised?
Synthesised from pregnenolone (by 3β-HSD in the corpus luteum) by the:
• Placenta during pregnancy
• Adrenal glands, as a step in androgen and mineralocorticoid synthesis
Mediation of progesterone actions?
Intracellular progesterone receptor, no. of which increase in the presence of oestrogen
Main productions of hormone synthesis at different phases in the menstrual cycle?
During follicular maturation - oestradiol
Luteal phase - progesterone (following ovulation)
Time period for ovulation and menstrual cycle?
Menstrual cycle begins on day 1 of the period
There are 2 phases following menses:
• Follicular phase - in the weeks leading up to ovulation
• Luteal phase - in the weeks following ovulation (progesterone peaks)
During ovulation, LH, FSH and oestrogen peak in levels
Definition of oligomenorrhea?
Reduction in frequency of periods to <9 per year
Definitions of primary and secondary amenorrhea?
Primary - failure of menarche by the age of 16 years (likely a congenital/genetic condition)
Secondary - cessation of periods for >6 months in an individual who has previously menstruated (likely an acquired cause)
Physiological causes of amenorrhoea?
- Pregnancy
2. Post-menopausal (usually >40 years of age)
Causes of primary amenorrhea?
Congenital problems, e.g:
• Turner’s syndrome
• Kallman’s syndrome
Causes of secondary amenorrhea?
Ovarian problem, e.g:
• PCOS
• Premature ovarian failure (can cause early menopause)
Uterine problem, e.g:
• Uterine adhesions
Hypothalamic dysfunction, due to e.g: • Stress • Weight loss • Exercise • Infiltrative causes
Pituitary, e.g:
• High PRL
• Hypopituitarism
Features of to check for in an amenorrhea history?
Symptoms of oestrogen deficiency:
• Flushing
• Libido
• Dyspareunia (painful intercourse)
Hypothalamic problem indications, e.g: weight loss, stress, exercise
Features of PCOS/androgen excess:
• Hirsutism
• Acne
Features of Kallman’s:
• Anosmia (loss of sense of smell)
Symptoms of hypopituitarism/pituitary tumour:
• Galactorrhea
Drugs assoc. with hyperprolactinaemia
Features to check for on examination of a patient presenting with amenorrhea?
Body habitus (for Turner’s)
Visual fields and anosmia
Breast development
Hirsutism, acne (androgen excess)
Ix that should always be done in a patient with oligo/amenorrhea?
LH, FSH and oestradiol
TFTs
Prolactin
Additional Ix for amenorrhea?
Ovarian USS +/- endometrial thickness (if it is thin, this indicates decreased oestrogen)
Testosterone (if there is hirsutism)
Pituitary function tests +MRI pituitary (if hypothalamic pituitary problems suspected)
Karyotype (if primary amenorrhea or features of Turner’s syndrome)
How is female hypogonadism detected?
Low levels of oestrogen
What is primary hypogonadism?
Problem with ovaries; there is a high LH/FSH (hypergonadotrophic hypogonadism)
Example is premature ovarian failure
What is secondary hypogonadism?
Problem with hypothalamus or pituitary; there is a low LH/FSH (hypogonadotrophic hypogonadism) and a low oestradiol
E.g: in high PRL, hypopituitarism
How to interpret LH/FSH measurements for a presentation of amenorrhea?
If high LH/FSH (esp. FSH):
• Primary ovarian problem
Low/inappropriately normal LH/FSH:
• Primary pituitary problem
• Hypothalamic problem
Presentation of premature ovarian failure (POF)?
Loss of ovarian function occurring <40 years of age with:
• Amenorrhea
• Oestrogen deficiency
• Elevated gonadotrophins
Diagnosis of premature ovarian failure?
FSH >30 on 2 separate occasions that are >1 months apart
Causes of premature ovarian failure?
Chromosomal abnormalities, e.g:
• Turner’s syndrome
• Fragile X
Gene mutations, e.g:
• In the FSH/LH receptor
Autoimmune disease, e.g: can be assoc. with:
• Addison’s disease
• Thyroid disease
• APS1/2
Iatrogenic, with radio/chemotherapy
Causes of secondary hypogonadism?
Hypothalamic problem:
• Functional hypothalamic disorders
• Kallman’s syndrome
• Idiopathic hypogonadotrophic hypogonadism (IHH)
Pituitary problems
Miscellaneous:
• Prader-Willi
• Haemochromatosis
Types of functional hypothalamic amenorrhea?
3 main types:
• Weight change related
• Stress related
• Exercise related
This can occur, e.g: in athletes, anorexia nervosa
Other causes of functional hypothalamic amenorrhea?
Anabolic steroids, recreational drugs
Iatrogenic, e.g: surgery/radiotherapy
Systemic illness
Infiltrative disorders, e.g: sarcoidosis
Head trauma
How is Idiopathic hypogonadotrophic hypogonadism (IHH) identified?
Absent/delayed sexual development assoc. with inappropriate low levels of gonadotrophin and sex hormone levels
There is an absence of anatomical/functional defects of the hypothalamic-pituitary-gonadal axis
Major defect in IHH?
Inability to activate pulsative GnRH secretion during puberty
Other features of IHH?
May have additional features:
• Anosmia (loss of sense of smell)
Pathogenesis of IHH?
Mutations in genes, some of which:
• Encode proteins that regulate GnRH neuronal migration
• Encode proteins that regulate GnRH secretion or GnRH action
Studies suggest there may be a mutation in a receptor for kisspeptin
What is KALLMAN’S SYNDROME?
Genetic disorder characterised by a loss of GnRH secretion + anosmia or hyposmia
More common in males and may be assoc. with an FH, although there are variable patterns of inheritance; shows genetic heterogeneity
Ix results in Kallman’s syndrome?
Normal remainder of pituitary function
Normal MRI pituitary, other than some absence of olfactory bulbs (related to anosmia, adue to close proximity of olfactory bulb to GnRH neurones in embryogenesis)
Main Ix results in PITUITARY DYSFUNCTION?
Low/normal LH/FSH
Low oestradiol
Causes of pituitary dysfunction?
Loss of LH/FSH stimulation:
• Non-functioning pituitary macroadenoma (pressure effects cause hypopituitarism)
• Empty sella
• Pituitary infarction
Hyperprolactinaemia: • Micro/macro prolactinoma • Drugs, e.g: dopamine antagonists, anti-psychotics • Hypothyroidism • Idiopathic
Ovarian causes of amenorrhea?
PCOS
Ovarian failure (high gonadotrophins)
Congenital problem with ovarian development, e.g:
Examples of congenital problems with ovarian development?
Anatomic:
• Uterus absence
• Vaginal atresia)
Genetic:
• Turner syndrome
• Testicular feminisation
• Non-classical and late onset CAH
What is Polycystic Ovarian Syndrome (PCOS)?
Set of symptoms that occur due to high androgens
Oestrogen levels are normal
Diagnosis of PCOS?
Using Rotterdam criteris:
- Menstrual irregularity
- Hyperandrogenism (hirsutism, elevated free testosterone)
- Polycystic ovaries
Other risk with PCOS?
Increased risk of diabetes and NAFLD, as increased testosterone causes insulin resistance and hyperinsulinaemia
What is hirsutism?
Excess hair, usually referring to women with male pattern hair distribution
Cause of hirsutism?
Androgen excess at hair follicle, due to:
• Excess circulating androgen
• Increased peripheral conversion at the hair follicle
Where does androgen biosynthesis occur?
In the ovaries and adrenal glands
Causes of hirsutism and the typical features of the different types?
Tend to have a long history and the testosterone is not dramatically elevated; there is no virilsation but may have deepening of voice and clitoromegaly:
• PCOS (most common cause)
• Familial, esp. Mediterranean population
• Idiopathic
• Non-classifical CAH
Tend to have a short history with signs of virilisation:
• Adrenal or ovarian tumour
What is Congenital Adrenal Hyperplasia?
Inherited group of disorders characterised by a deficiency in one of the enzymes necessary for cortisol synthesis, usually 21α-hydroxylase; autosomal recessive
Features of classic CAH?
Tends to be diagnosed in infancy with virilisation and salt-wasting
Features of non-classic CAH?
Partial 21α-hydroxylase deficiency
Presents in adolescence/adulthood with:
• Hirsutism
• Menstrual disturbance
• Infertility (due to anovulation)
Ix for CAH?
Synacthen test
Presentation of androgen-secreting tumours?
Rapid onset and is usually assoc. with signs of virilisation
Ix for androgen-secreting tumours
High testosterone (>5 nmol/L)
MRI adrenal glands and ovaries (demonstrate tumours >1 cm)
Treatment of hyperandrogenism?
Depends on cause
Treatment of PCOS?
Oral contraceptive pill (regulates cycle and decreases ovarian androgens)
Anti-androgens, e.g: cyproterone acetate (often combined with the oral contraceptive pill as Dianette)
Local anti-androgens: Efflornithine cream (Vaniqa)
Cosmesis, e.g: electrolysis or laser phototherapy
Treatment of non-classic, late onset CAH?
Low dose glucocorticoid to suppress ACTH drive
Karyotype in Turner’s syndrome?
XO, i.e: female only has one X chromosome; other genotypes are less common (mosaicism)
Thus, it only affects women
Main features of Turner’s syndrome in paediatrics?
Short stature
Webbed neck
Shield chest with wide-spaced nipples
Cubitus valgus
Lymphoedema
Failure to progress through puberty (normal adrenarche, breast development may be normal)
Main features of Turner;s syndrome in adults?
Primary or secondary amenorrhea
Infertility
Other problems assoc. with Turner’s syndrome?
CVS:
• Coarctation of the aorta
• Bicuspid aortic valve
• Hypoplastic left heart
GI
• Bleed (vascular malformation)
• Increased Crohn’s/UC
Other: Lymphoedema • AI hypothyroidism • Osteoporosis • Scoliosis • Otitis media • Some have renal anomalies
What is XX gonadal dysgenesis?
Absent ovaries but no chromosomal abnormality
Describe testicular feminisation
Androgen insensitivity syndrome; the male is genetically XY but, in the complete form, phenotypically females
i.e: pseudohermaphrodires
Types of male hypogonadism?
Primary:
• Low testosterone with high LH/FSH
• Acquired and congenital causes, e.g: Klinefelter’s
Secondary:
• Low testosterone with inappropriate low LH/FSH
• Pituitary/hypothalamic disease
History features of hypogonadism?
Sexual function (libido, erections, ejaculation)
Age of puberty, shaving frequency, etc
Fertility
Symptoms of pituitary disease
Duration of symptoms/features (permanent vs acquired)
Other relevant history, e.g: trauma, infection, chemo/radiotherapy, etc
Signs of hypogonadism?
Staging of puberty (secondary of sexual characteristic)
Testicular volume
Visual fields/other pituitary disease
Flow chart for investigations of hypogonadism?
ADD PICTURE
What is Klinefelter’s syndrome?
Most common congenital form of primary hypogonadism; the karyotype is 47 XXY (or mosaicism)
Ix results in Klinefelter’s syndrome?
Low testosterone
High LH/FSH (elevated SHBG or oestradiol)
Causes of secondary hypogonadism in men?
Congenital/idiopathic:
• IHH, inc. Kallman’s syndrome (i.e. with anosmia)
• CAH
Functional:
• Exercise, weight change, stress, systemic illness
• Infiltrative disorders (e.g:
cranial irradiation / trauma)
• Drugs (e.g: anabolic steroids, opiates)
• Hyperprolactinaemia
• Hypothalamic or pituitary tumours / surgery
• Prader-Willi syndrome
Testosterone replacement in male hypogonadism?
Indicated in young men but less clear in older men, i.e: >50 years
It does not restore fertility (may actually act as a contraceptive)
Potential health benefits of testosterone replacement in male hypogonadism?
Improved sexual function (more effective in younger men)
Bone health (improves BMD)
Body composition/muscle strength
Insulin sensitivity (possible small improvement in insulin sensitivity, minimal effect on HbA1c)
Why does gynaecomastia occur?
Increased oestrogen action on breast tissue
Causes of gynaecomastia?
Physiological
Drugs (oestrogens, testosterone, spironolactone, digoxin, etc)
Hypogonadism
Tumours:
• Oestrogen/androgen testicular or adrenal origin
• hCG secreting, e.g: germinoma
Endocrine disorders, e.g: thyrotoxicosis, Cushing’s
Systemic illness
Hereditary disorders
Taking a history of gynaecomastia?
Duration of symptoms
Pain?
Symptoms of hypogonadism OR of systemic disease
Recreational drugs/alcohol
Examination of gynaecomastia?
Breast tissue vs fat Unilateral/symmetrical Any hard irregular nodules Examination of testes (e.g: tumour) General examination (e.g: liver disease)
Ix fo gynaecomastia?
- Testosterone, LH, FSH
- Oestradiol
- Prolactin
- AFP, HCG
- LFTs
- SHBG
Breast imaging
Testicular/adrenal imaging
Treatment of gynaecomastia?
Address underlying cause (e.g: remove causative drugs) and reassurance
Surgery (cosmetic)
Medication (e.g: anti-oestrogens)
