Reproductive endocrinology

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Reproductive endocrinology

• Robert Schmidli FRACP, MRCP, PhD
• Senior Lecturer, ANU Medical School

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Primary gonadal failure
Pituitary
Insult
LH, FSH
Ovary/testis
Estrogen/ Testosterone
Clinical hypogonadism
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Secondary gonadal failure
Insult
Pituitary
LH, FSH
Ovary/testis
Estrogen/ Testosterone
Clinical hypogonadism
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Male hypogonadism
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Clinical features Time of onset

• First trimester female genitalia, ambiguous
  genitalia, virilisation
• Third trimester micropenis, cryptorchidism
• Childhood, adolescence delayed puberty,
  eunuchoid proportions (? long bone length)
• Adult
• Decreased libido, erectile dysfunction
• Fatigue
• Loss of muscle mass
• Reduced facial, body hair
• Loss of bone mass
• Gynaecomastia (1 gt 2)
• ? sperm count (1 gt 2)

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Laboratory assessment - Testosterone

• Total testosterone well standardised, widely
  used in decision making
• Free testosterone by equilibrium dialysis not
  widely available
• SHBG, FAI not useful in males
• Peaks at 8am, minimum (80 of peak) at 8pm
• Repeat total of 2-3 times if borderline

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Investigation

• LH, FSH primary vs secondary
• Semen analysis
• Primary
• Karyotype
• Secondary
• Pituitary function
• MRI pituitary
• Prolactin
• Iron studies

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Primary Hypogonadism Causes

• Idiopathic
• Klinefelter syndrome
• Chemotherapy
• Radiotherapy
• Cryptorchidism (subnormal sperm, high FSH,
  variable)
• Chronic disease
• Trauma
• Bilateral orchidectomy
• Glucocorticoids
• Torsion
• Mumps orchitis
• Myotonic dystrophy (mainly ?sperm, ?FSH)
• Autoimmune
• Ketoconazole (inhibits testosterone synthesis)

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Klinefelter syndrome

• XXY. X gt 2 and mosaic possible
• 11000 male live births
• Testicular development translocation of small
  portion of testis-determining factor to X
  chromosome
• Subnormal sperm count, infertility
• Small testes
• Increased leg length (Testo deficiency)
• Variable testosterone deficiency, ?LH, FSH
• Psychosocial abnormality (in some)
• Higher risk of breast cancer, lung disease,
  cancer, germ cell tumours etc

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Secondary hypogonadism

• LH/FSH deficiency
• Pituitary lesions
• Hyperprolactinaemia
• Congenital hypogonadotrophic hypogonadism eg
  Kallman syndrome
• Testosterone secretion in 1st trimester
  controlled by hCG ? male phenotype
• Micropenis, cryptorchidism
• Anosmia
• Midline defects

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Hypogonadism and ageing

• Gradual onset, relatively modest cf female
  menopause
• Difficulties
• Normal range difficult to define
• Risks vs benefits of treatment not known
• Gradual fall with age normal 0.4pa
• ?SHBG ? ?free testosterone

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Consequences

• Unknown with certainty
• Several parallels
• Sexual function
• ?BMD
• ?Muscle and ?fat mass
• Mood, cognitive function
• CV risk factors
• Effects of testosterone administration
• Controversial, small studies
• More conservative approach recommended

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Harmful effects of treatment

• Erythrocytosis, polycythemia
• May increase CV morbidity
• Check for other causes
• Prostate cancer
• Studies not adequately powered
• Increased in meta-analysis ?ascertainment bias
• Prostatic hyperplasia studies too small
• Sleep apnoea conflicting data
• ?HDL
• CV disease no evidence

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Treatment

• Should only treat hypogonadal males
• Testosterone rapidly metabolised by liver
  ineffective orally
• Testosterone esters useful for depot
• Can be given transdermally, buccal, pellets

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Treatment of infertility

• Klinefelter synd occasional pregnancy with sperm
  retrieval intra cytoplasmic sperm injection
• Hyperprolactinaemia dopamine agonist
  gonadotrophins
• Hypogonadotrophic
• Human chorionic gonadotrophin (hCG) equivalent
  to LH. May be effective alone
• Human menopausal gonadotrophin (hMG) or
  recombinant FSH
• Pulsatile GnRH

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Gonadal disorders in females

• Primary amenorrhoea
• Secondary amenorrhoea
• Polycystic ovary syndrome
• Infertility

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Primary amenorrhoea

• Absence of menses by 15y in presence of normal 2
  sexual characteristics
• Causes
• Chromosomal
• Hypothalamic
• Anatomic
• Pituitary

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Hypothalamic/pituitary

• Functional eg. anorexia nervosa, exercise
• GnRH deficiency eg Kallman syndrome
• Constitutional delayed puberty
• Hyperprolactinaemia
• Pituitary lesions

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Ovarian disease

• Turner syndrome commonest (45,X)
• Normal genital development until puberty
• Dysmorphic features
• Variants of gonadal dysgenesis 45,X/46XX
  mosaic, 46,XY
• 46,XY have high risk of gonadoblastoma or
  dysgerminoma removal required
• Fragile X
• Polycystic ovary syndrome

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Secondary amenorrhoea

• Absence of 3 cycles or 6 months, if previous
  menses
• Etiology
• Pregnancy
• Functional hypothalamic amenorrhoea
• Hypothalamic/pituitary disease
• Systemic disease
• Hyperprolactinaemia (GnRH suppression)
• Thyroid dysfunction
• Polycystic ovarian syndrome
• Premature ovarian failure
• Uterine disease

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Polycystic ovary syndrome

• Variable clinical presentation, probably
  multifactorial etiology
• NIH (1990) requirements
• Menstrual irregularity due to oligo/anovulation
• Clinical or biochemical hyperandrogenism
• Absence of other causes
• Rotterdam (2003) two of
• Oligo/anovulation
• Clinical or biochemical hyperandrogenism
• Polycystic ovaries (by ultrasound)
• Absence of other causes

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Laboratory evaulation

• Testosterone, sex hormone binding globulin
• Adrenal androgens
• DHEAS
• Androstenedione
• 17-OH Progesterone (CAH)
• LH (may be elevated)
• Ovarian ultrasound
• High level expertise required
• Cysts may be non-specific
• Lipids, glucose, C-peptide

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Differential diagnosis of PCOS

• Hyperprolactinaemia
• Nonclassical congenital adrenal hyperplasia
• No adrenal insufficiency
• Treatment often same as other causes of
  hirsuitism
• Often not pursued
• Androgen-secreting tumours
• Cushings Syndrome

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Female infertility diagnostic approach

• Confirm ovulation
• Regular menses symptoms ? probably ovulating
• Day 21 (mid-luteal) progesterone
• Semen analysis
• Overlap between fertile/infertile men
• Tubal occlusion
• Ovarian reserve Anti-mullerian hormone
• member of TGF-ß family
• reflects size of primordial follicle pool