Week 1 Flashcards
Hypothalamus
Region found at base of brain between midbrain and forebrain
Collection of brain nuclei or centres
Controls endocrine function via pituitary gland
Gonadotropin releasing hormone GnRH
Peptide hormone
Decapeptide derived from 92 aa prepropeptide
Kallmann syndrome: failure of GnRH secreting neurons to migrate during development- infertility
At puberty gonadal activation is triggered by activation of pulsatile GnRH secretion
In males frequency of pulses is fairly constant (every 2-3 hours)
In females varies during menstrual cycle- medium frequency-> FSH, high frequency -> LH, low frequency- luteal phase
Other factors also regulate FSH/LH eg E2, P4, inhibin
Continuous GnRH leads to down regulation of GnRHR on surface of gonadotroph cells in pituitary- no stimulation of FSH/LH release
Possible to block GnRH effects using an antagonist or agonist
Pituitary (hypophysis)
Pea sized gland at base of brain
Secretes a range hormones regulated by signals from hypothalamus and feedback loops involving circulating hormones
Anterior: ACTH, TSH, GH, LH, FSH, prolactin
Posterior: ADH, oxytocin
Anterior pituitary hormones important in reproduction
Gonadotropins- gonadotrophs
-follicle stimulating hormone FSH
-luteinising hormone LH
Proteins and peptides:
-adrenocorticotropic hormone ACTH- corticotrophs
-growth hormone GH- somatotrophs
-prolactin- lactotrophs
Gonadotropins
HPG axis- FSH and LH
(HCG)
Glycoproteins
Bind receptors on cell surface and signal via G-proteins
Luteinising hormone LH
Secreted by gonadotrophs (ant. Pit)
Acts on leydig, theca and granulosa cells
Structure: common alpha chain (116 aa), unique b chain (121aa), one N-linked carbohydrate chains
Receptor: LHCGR
Follicle stimulating hormone FSH
Secreted by gonadotrophs (ant.pit)
Acts on sertoli and granulosa cells
Structure: common a chain (116aa), unique b chain (111 aa) two n linked carbohydrate chains
Receptor: FSHR
Chorionic gonadotrophin hCG
Secreted by syncytiotrophoblasts (embryo)
Acts on luteal cells (corpus luteum)
Structure: common a chain (116 aa), unique b chain (145 aa), two n linked and four o linked carbohydrate chains
Receptor: LHCGR
Communication hypothalamus-> pituitary
- Direct i.e neural to posterior pituitary
- Indirect i.e vascular to anterior pituitary
Sex steroids
All derived from cholesterol (via acetate)
Three families:
-progestagens- pregnancy (placenta)
-androgens- maleness (<5% adrenals)
-oestrogens- femaleness (liver, adrenals, adipose, placenta)
Some exceptions
Lipid soluble- nuclear receptors
Act via steroid response elements (SREs)
Bound to carrier proteins- albumin, sex hormone binding globulin (SHBG), androgen binding protein (ABP)
Progestagens
Progesterone P4
17 a- hydroxyprogesterone 17a-OHP
20a-hydroxyprogesterone 20a-OHP
Functions: preparation and maintenance of endometrium (pregnancy), development of mammary glands, suppression of lactation, catabolic effects, regulation of gonadotropins
Receptors: PR-A and PR-B (PR-B has additional 164 aa) activate different genes
Androgens
5a-dihydrotestosterone DHT
Testosterone T
Androstenedione (A4)
Dehydroepiandrosterone (DHEA)
Functions: development and maintenance of male reproductive system, development of secondary sexual characteristics, sexual function, supports spermatogenesis, regulation of gonadotropins
Receptors: AR-polymorphic in exon 1 with isoforms showing differing sensitivities to androgen levels
Oestrogens
Oestradiol 17β (E2)
Oestriol (E3)
Oestrone (E1)
Reproductive Functions: development of secondary sexual characteristics Stimulate development and function of mammary glands Stimulate proliferation of endometrium for progesterone action Regulate gonadotropins
Receptors ERα and ERβ
Puberty to menopause – oestradiol
Pregnancy – oestriol
Post-menopause - oestrone
Potency
Depends on how well steroid ‘fits’ binding site on receptors
Varies within each class
Some bind receptors from other classes eg synthetic progestagens in contraceptive pill can be androgenic- side effects eg acne
Some bind but dont activate ie act as antagonists eg mifepristone (RU486)- anti-progestagen
Clinical problems- HPG axis
Affect fertility
Hypothalamus/pituitary- central or secondary hypogonadism- low FSH/LH
Ovary/testes- peripheral or primary hypogonadism -lack of feedback- high FSH/LH
GnRH rarely measured
Endocrine problems are a common cause of female fertility problems much less for men
Prolactin
Levels increase dramatically in pregnancy and during breast feeding
Inhibits gonadal activity through central suppression of GnRH (and thus decreased LH/FSH)
Induces lactational amenorrhea- family spacing
Hyperprolactinaemia- galactorrhea
Menstrual cycle- clinically
Normal duration= 26-32 days (average 28 days)
Luteal phase- 14 days, follicular phase varies
Day 1= first day of menses
FSH/LH- day 2 or 3- ovarian reserve
Testing for ovulation- P4 day 21/28
Oligomenorrhea- <9 cycles in last 12 months
Amenorrhea- no bleed in last 6 months
Primary (never) or secondary (ceased)
Menorrhagia, dysmenorrhea