E7- DIsorders of the gonads

What is the function of gonads

• hormone production

• gomete production

Define hypogonadism

Decresed functional activity of the gonads

What are the classifications of hypogonadism

• onset time

  • fetal, prepubertal, post pubertal

• genetic alterations

  • congenital, acquired

• HPG axis

  • organic, functaional

• location of disruption of HPG axis

  • primary, secondary

What is the difference in primary and secondary hypogonadism

What is the difference between hypergonadotropic and hypogonadotropic hypogonadism

• hypergonadotropic- primary= high LH, FSH

• hypogonadotropic- secondary= low LH, FSH

Define female hypogonadism

during the age range from normal puberty to normal menopause= amenorrhea

with

• deficiency ovarian folliculogenesis

• impaired sex hormone secreteion

• anovulation

• sexual or vasomotor symptoms

What are the types of amenorrhoea

• primary

  • no cycles at age of 16

• secondary

  • > 3 cycles lacking- if cycles were regular previously

  • >6 months lacking- if cycles were irregular before

What is the biochemical cause of amenorrhoea

Persistently low circulating serum 17 beta estraadiol concentration

What is it when there is amenorrhea and elevated LH/FSH

Premature ovarian insufficiency

What is it when there is amenorrhea and low/ normal LH. FSH

Central hypogonadism

What are the types of premature ovarian insufficiency

• Turner syn

• Autoimmune

• Iatrogenic

• Single gene defect

What are the types of central hypogonadism

• Congenital hypogonadotrophic hypogonadism

• hypothalamic amenorrhea

• hypopituitarism

• other- opioids, diabetes, obesity

What is the diagnostic workup inn premature ovarian insufficiency

• personal and family history

• karyotype

• FMR1 gene screening for fragile X syndrome

  • mental retardation, tremor/ ataxia, ovarian failure

• TSH

• thyroid peroxidase antibody

What are the autoimmune causes of premature ovarian insufficiency

Autoimmune oophoriti- Selective theca cell destruction

What are the iatrogenic causes of premature ovarian insufficiency

• irradiation

• chemotherapy

• ovarian surgery

What are the single gene defect causes of premature ovarian insufficiency

FRMC gene mutation

What is turner syn

Chromosomal disorder that affects phenotypic females who have 1 intact X chromosome and complete or partial absence of the second sex chromosome in association with one or more clinical manifestations

• 45 X

What are the features of Turner syn

• short stature

• low hairline

• early sensorineural hearing loss

• shield shaped thorax

• constriction of aorta

  • coarction of aorta, bicuspid aortic valve

• elbow deformity

• underdeveloped gonadal structures

What are the indications for chromosomal analysis in Turner syn

• only clinical feature

  • fetal cystic hyfroma, hydrops

  • idiopathic short stature

  • obstructive left sided congenital heart defect

  • unexplained delayed puberty

  • couple with infertility

• at least 2 of the following

  • renal anomaly- horseshoe, absence, hypoplasia

  • neuropsychologic problems

  • dysplastic or hyperconvex nails

  • hearing impairment

What are the most common abnormalities assiciated with Turner syn

• Endocrine

  • growth failure

  • glucose intolereance

  • type 2 DM

  • hypothyroiditis

  • decreased bone mineral content

• GI, hepatic

  • increased hepatic enzymes

  • celiac

  • IBD

• Neurocognitive, psychosocial

  • emotional immaturity

  • specific learning disorder

  • psychological and behavioural problems

• CV

  • bicuspid aortic valve

  • coarction of aorta

  • aortic dilation/ aneurysm

  • hypertension

What is the treatment of h=Tyrner syndrome

• Growth hormone- recombinant hGH

  • initiation- 4-6yo, before 11-12yo

  • GH dose (4.0–4.5 IU/m2/day)

• Hormone replacement therapy

What are the types of congenital isolated hypogonadotropic hypogonadism

• Asosmic- Kallmann syn

• Normosmic CHH

What is Kallmann syndrome

Problem with development and migration of GnRH neurons

• low LH, FSH

What is normosmic CHH

Genes that affect synthesis and secretion of GnRH

What are the associated abnormalities of CIHH

• renal agenesis

• hearing loss

• midline defects- cleft lip/ palate

• dental and skeletal anomalies

What are the causes of hypothalamic amenorrhoea

• genetic disorders- Prader Wili

• functional causes- inhibited hypothalamus

• structural causes

What is Prader Wili syndrome

• genetic neurodevelopmental syndrome

• absence of expression of paternally active genes on the long arm of chromosome 15

• hypothalamic pituitary dysfunction with severe hypotonia and feeding deficits during neonatal perio

• followed by an excessive weight gain period with hyperphagia + risk of severe obesity during childhood and adulthood

What is the clinical manifestation of PWS

• hypogonadotropic hypogonadism

• behavioural issues

• learning difficulties

• symptoms of hyperphagia with progressive development of obesity

What is functional causes of hypothalamic amenorrhoea

Suppressed hypothalamus

• surgery, brain injuries, myocardial infarctionm, stroke, sepsis

• hyperprolactinemia

• restricted nutritional intake

• low fat mass- restricted nutritional intake exercise

What are the goals of female HRT

• treatment to restore normal menstrual cycle

• possible fertility

• enhancement of secondary sexuality

• increase bone mineral content

What is the femalr HRT

• estrogen monotherapy- if there is no uterus

• Estrogen/ progestin regime- if intact uterus

  • progestin to prevent estrogen induced endometrial hyperplasia and carcinoma

  • Estrogen- transdermal, vaginal. oral estradiol

  • progestin- micronised progesterone daily for a month or medroxyprogesterone acetate daily for a month

What are the side effects of female HRT

• impaired liver function tests

• hypertension

• DVT- pulmonary embolism

What are the absolute contraindications of female HRT

• endometrial and breast carcinoma

• active DVT, PE

• active liver disease

What are the other causes of prolonged amenorrhoea

• hyperandrogenism in female

What is hyperandrogenism in females

• Medical condition characterised by high levels of androgens

• PCOS, androgen secreting adrenal/ ovarian tumours

What is the grading of hyperandrogenism in females

Ferriman Gallway score

• 9 different areas of the body are scored for presence of hair

• score of 9+ is considered diagnostic of hirsutism

Describe PCOS

• most common disease in women

• 5-15% affected in reproductive age

• most common cause of anovulation, infertility

• clinical symptoms start in adolescence + seen at later stages in life

What are the components of PCOS

• hyperandrogenism

• irregular menstrual cycles

• bilateral ovaries with enlarged, immature follicles

What is the course of PCOS

What is the pathophysiology of PCOS

How do you diagnose PCOS

Rotterdam criteria 2/3

• irregular menstrual cycles

• clinical and/or biochemical hyperandrogenism → LH/ FSH ratio >2

• polycistic ovaries on ultrasound

  • or AMH determination may be used instead of ultrasound

  • follicle number per ovarium, per secretion and ovarian volume

How do you use AMH to diagnose PCOS

• AMH is secreted by granulosa cells of immature follicles

• AMH determination can be used to confirm PCOS but only in adults

What is the treatment goals of PCOS

• Amelioration of hyperandrogenic features

  • hirsutism, acne, scalp hair loss

• management of metabolic abnormalities + reduce risk of T2DM an CV disease

• prevent endometrial hyperplasia and carcinoma

  • as a result of chronic anovulation

• contraception- oligomenorrhoea ovulate intermittently and unwanted pregnancy prevention

• ovulation induction for those wanted kids

What are the treatment approaches for PCOS

• lifestyle changes- diet, weight reduction

• androgen treatment for irregular cycles

  • oral contraception

  • metformin

  • low dose spironolactone

  • ovulation induction medication- clomiphen citrate

• treatment of infertility

  • letrozol

  • gonadotropins with US monitoring

  • ovarian drilling

  • IVF

What are other potential causes of prolonged amenorrhoea

Androgen secreting adrenal/ ovarian tumours

• rare

• severe hyperandrogenism- virilisation

• significant increase in serum T >200ng/dl

• imaging- TVS, pelvic MRI

• Leydig, sertoli, hilus cell tumours

• usually benign

• treatment- surgical removal

What are symptoms of male hypogonadism

• melancholy

• loss of libido

• visceral adiposity

• insulin resistance

• osteoporosis

• infertility

• erectile dysfunction

• loss of muscle mass

• anemia

Describe the eunochoid body

• lack of closure of epiphyseal plates

  • limbs disproportionate to trunk

• gynecomastia, female pubic hair pattern

• insufficient testicular and penile growth

• osteoporosis, lack of masculine muscle mass

What is the classification of male hypogonadism

• Primary

  • testicular

• secondary

  • hypothalamic causes

  • pituitary causes

• target organ resistance

  • androgen receptor resistance

  • 5 alpha reductase deficiency

• age related hypogonadism

  • late onset

What are the testicualr causes of male hypogonadism

• Klinefelter syn

• orchitis

• testicular maldescent

• testicular tumours

What are the hypothalamic causes of secondary male hypogonadism

• congenital HH

  • normosmic, anosmic- Kallmann syn

• constitutional delay of growth and development

What is Klinefelter syndrome

• most common cause of primary hypogonadism-gonadal dysgenesis

• only 25-50% of patients are diagnosed

• 47 XXY (XXXY, XXXXY, XXYY)

• phenotype of Klinefelter is affected by androgen responsivenes

• Total T and free T decrease/ FSH increased

What is the clinical presentation of Klinefelter syndrome

• Neonatal- micropenis, hyopspadias or cryptorchidism

• teen- delayed puberty

• adults- small testes and androgen deficiency or infertility

  • gynecomastia, ED, osteoporosis

  • oligo azoospermia

  • very small, firm testes

What are the common morbidities of Klinefelter syn

• emphysema

• COPD

• T2DM

• risk of breast cancer

• autoimmune disease

What is the treatment of Klinefelter syndrome

• Lifelong T replacement

  • prevent osteoporosis, obesity, metabolic syndrome, diabetes

• treat reduced fertility

  • surgical extreaction of sperm from testes

• life long care- due to comorbidities

What are rare causes of testicular primary/ hypergonadootrop hypogonadism

• Del Castillo syndrome/ Sertoli cell only syndrome

• Noonan syndrome

• Myotonic dystrophy

• Kartagener syndrome

What is Del Castillo syndrome/ Sertoli cell only syndrome

• microdeletions in the long arm of the Y chromosome

• Testicular biopsies : germinal cell maturation arrest or Sertoli cell-only syndrome

• FSH↑, LH, testosteronenormal

What is Noonan syndrome

• bothgendercanbe affected

• autosomaldominant, cryptorchidism, testicular hypogonadism

• likeTurner systigmas( without renal disease and aortic stenosis)

• Atrial septumdefect, valvular pulmonal stenosis

• 46XY, 6-12 chromosomeparcial deletion

What is myotonic dystrophy

• Myotonic dystrophy is an autosomal disorder with delayed onset (age 30 to 40 years) of impaired motor function

• testicular hypogonadism, cataracts, premature frontal balding, mild mental retardation, and infertility

What is Kartagener syndrome

• dynein defect- immobilised sperm

• situs inversus, bronchial disease

What is androgen insensitivity syndrome

• synonym- testicular feminisation/ androgen receptor dysfunction

• genetic origin- mutations that cause impairment of androgen receptor

• X linked recessive

• 46 XY

• phenotype depends on residual androgen receptor activity

  • complete, partial, mild androgen insensitivity syndrome

What is the treatment of male hypogonadism

• androgen substitution if patient wants children

• testosterone supplementation

• GnRH supplementation in HG

• dopamine agonists in hyperprolactinaemia

What is the treatment for primary male hypogonadism

T replacement

• ROA- depot IM injection, transdermal gel

• SE- acne, oily skin, breast tenderness, HDL chol decrease, increased RBC, azoospermia

• contraindication- prostate cancer, elevated liver function or liver neoplasm

What do you need to monitor during HRT in male primary hypogonadism

• Testosterone levels (initially every 3 months then 6-12m)

• Hematocrit levels (every 6-12 months)

• Liver function tests (every 6-12 months)

• PSA (annually) Abdominal (liver) ultrasound (annually)

What is the treatment of hypogonadotrophic hypogonadism

1. androgen substitution and/or LH-FSH (to have childbearing potencial)

   1. LH analogs: HCG treatment → Leydig cell T secretion

2. long-term testosterone treatment if the patient has no active intention to have children

3. dopamine agonists: in cases of hyperprolactinemia:

4. clompihen-citrate: in mild HH