HPO Axis (infertility, menopause etc) Flashcards
Role of hypothalamus in HPO axis?
Controls cycle but influenced by higher centres (e.g. stress, anxiety).
Secretes decapeptide gonadotrophin-releasing hormone (GnRH) in a pulsatile manner (approximately every 90 mins).
GnRH travels through small blood vessels of pituitary portal system –> basophil cells of anterior pituitary (stimulates FSH/LH synthesis & release).
Constant high dose GnRH desensitises the GnRH receptor + reduces FSH & LH release ∴ GnRH agonists (buserelin, gosrelin) reduce FSH/LH & this also affects ovarian function (↓ oestrogen & progesterone), so most women become amenorrhoeic. These agonists used as treatment for endometriosis & to shrink fibroids prior to surgery.
Role of the pituitary in HPO axis?
How does oestrogen/progesterone affect this?
Synthesis + release of gonadotrophic hormones (FSH + LH) - stimulated by GnRH + modulated by ovarian sex steroid hormones (oestrogen + progesterone).
Low oestrogen inhibits LH (negative feedback - mechanism uncertain). High oestrogen increases LH (positive feedback - mechanism via increased GnRH). The COCP artificially creates a constant serum oestrogen level (in the negative feedback range) which results in a low level of gonadotrophin release.
Unlike oestrogen, low progesterone levels has a positive feedback effect on FSH + LH and contributes to the FSH surge before ovulation (pituitary becomes more sensitive to GnRH). High progesterone (luteal phase) inhibits pituitary FSH/LH production (pituitary becomes less sensitive to GnRH, and hypothalamus produces less GnRH). Progesterone can only have these effects on gonadotrophin release after priming by oestogen.
What is FSH?
Follicle-stimulating hormone (FSH): glycoprotein which stimulates growth of follicles (during follicular phase) & stimulates sex hormone secretion (primarily oestradiol by granulosa cells of mature ovarian follicles).
What is LH?
Luteinising hormone (LH): glycoprotein which stimulates sex hormone production (testosterone, which is converted to oestradiol by action of FSH). High levels of circulating oestrogen (late follicular phase) generates a periovulatory LH surge from the pituitary (via the positive feedback mechanism). The mid-cycle surge of LH also triggers rupture of the mature follicle with release of the oocyte. LH also influences the post-ovulatory production of progesterone by the corpus luteum.
What is inhibin and activin?
Peptide hormones produced by granulosa cells in ovaries
Inhibin inhibits pituitary FSH secretion
Activin stimulates FSH secretion
Length of normal cycle? Highest contractility? What factors are needed to have a normal cycle?
Normal cycle: 24-32 days (28 average). Greatest uterine contractility in first 48 hours.
Requires intact HPO axis, responsive follicles in ovaries & functional uterus. Described in terms of the ovarian cycle or the endometrial cycle.
What are the stages of the ovarian cycle?
- Follicular phase (day 1-14)
- Ovulation (day 14)
- Luteal phase (15-28)
What is happens in the follicular phase?
FSH + LH stimulates development of 10-20 follicles (primordial follicles contain oocytes) + the dominant follicle appears during the mid-follicular phase (remainder undergo atresia). The dominant follicle is most sensitive to FSH –> full maturation and ovulation. Growth of the dominant follicle associated with ↑oestrogen. Note: initial stages of follicular development are independent of hormone stimulation, but follicular development will fail at preantral stage and follicular atresia follows if FSH + LH are absent.
Day 1-8 of follicular phase?
↓ Oestrogen, progesterone + inhibin at menstruation causes ↑FSH & LH. Rising FSH stimulates a cohort of small antral follicles to grow on the ovaries. Within the follicles, theca cells & granulosa cells are both involved in processing steroids.
• LH stimulates the conversion of cholesterol > androgens within theca cells.
• FSH stimulates aromatisation (androgens > oestrogens) within granulosa cells
As the follicles grow and oestrogen secretion increases, negative feedback on pituitary decreases FSH secretion. This assists in selection of 1 dominant follicle (if most efficient aromatase activity + highest concentration of FSH-induced LH receptors, more likely to survive as FSH levels drop).
Day 9-14 of follicular phase?
As the follicle increases in size, localised accumulations of fluid appear among the granulosa cells + become confluent –> antrum (fluid-filled central cavity). This transforms the primary follicle –> Graafian follicle (>10mm), where oocyte occupies eccentric position surrounded by 2-3 layers of granulosa cells (the cumulus oophorus).
Progressive ↑oestrogen (mainly oestradiol) produced by granulosa cells of dominant follicle causes suppression of gonadotrophin release (FSH & LH) by negative feedback. The granulosa cells also produce inhibin (may restrict number of follicles undergoing maturation, and enhances androgen synthesis under LH control).
- Inhibin: produced by testicles in men & granulosa cells in women: downregulates FSH release and enhances ongoing androgen synthesis
- Activin: structurally similar, produced by granulosa cells and in the pituitary: increases FSH binding on follicles (i.e. opposing effect to inhibin).
Others: IGF-1 is produced by theca cells under action of LH in the follicular phase. IGF-1 receptors are on theca + granulosa cells and IGF-1 augments LH-induced steroidogenesis (paracrine action): enhances LH-induced progesterone production. Kisspeptins recently found to have role in HPO regulation via mediation of leptin on the hypothalamus (mutations in gpr-54, a kisspeptin receptor, associated with delayed/absent puberty, likely due to reduced leptin-linked triggers for gonadotrophin release).
Note: exogenous gonadotrophins likely to stimulate growth of multiple follicles which continue to develop & are released at ovulation (can lead to multiple pregnancy rate ~30%). Advantageous in IVG (harvest many oocytes to undergo fertilisation process & transfer surviving embryos back).
What happens at ovulation (Day 14)?
Day 14: Rapid enlargement of follicle > protrusion from surface of ovarian cortex > rupture of follicle with extrusion of oocyte & adherent cumulus oophorus.
Some women experience short-lived pain in one iliac fossa (‘mittelschmerz’ – occurs just before follicular rupture in USS studies).
Final rise in oestradiol concentration thought to cause subsequent mid-cycle surge of LH (and FSH to a lesser extent) by positive feedback. Ovulation occurs within 18 hours of the mid-cycle LH surge. Immediately before ovulation: fall in oestradiol and increase in progesterone. The LH-induced luteinisation of granulosa cells (in the dominant follicle) causes progesterone production (further increases the positive feedback + LH surge + causes a small rise in FSH). Androgens synthesised by theca cells also rise around this time (thought to have role in stimulating libido).
What is the luteal phase?
Day 15-28: Remainder of the Graafian follicle (retained in the ovary) is penetrated by capillaries + fibroblasts from the theca. Granulosa cells undergo luteinisation –> corpus luteum (major source of oestrogen & progesterone in post-ovulatory phase). There is marked ↑progesterone + 2nd rise in oestradiol levels.
Progesterone peaks 1 week after ovulation (day 21: serum progesterone used as fertility test). ↓Gonadotrophin: remains low until regression of corpus luteum (day 26-28). If no conception/implantation, corpus luteum regresses, progesterone falls + menstruation begins. Fall in sex hormones allows FSH + LH to rise + initiate next cycle. If conception + implantation: hCG secreted by the trophoblast (this maintains the corpus luteum).
(Following ovulation, IGF-II produced by luteinised granulosa cells and acts in autocrine manner to augment LH-induced proliferation of granulosa cells).
What is the endometrial cycle?
- Proliferative phase
- Secretory phase (after ovulation, endometrial growth stops + glands more active)
- Menstrual phase
Endometrium: superficial layer + basal layer (which regenerates the superficial layer). Junction between layers: change in arterioles supplying endometrium (straight arterioles traversing basal layer, convoluted spiral section traversing superficial layer).
Proliferative: endometrium exposed to oestrogen during follicular phase > oestradiol from ovary causes endometrial repair & regeneration. Ongoing growth and proliferation of glands and vessels. Glands are tubular and arranged in regular parallel pattern.
Secretory: progesterone production post-ovulation induces secretory changes in endometrial glands (prepares for implantation). Secretory vacuoles develop in the glandular epithelium and glands become tortuous with serrated margins.
Menstrual: regression of corpus luteum associated with ↓ oestrogen/progesterone > intense spasmodic contraction of spiral arterioles > ischaemic necrosis > shedding of superficial layer. Vasospasm caused by local prostaglandin production (may also account for increased uterine contractions during menstrual flow). Local fibrinolytic activity in endometrial blood vessels peaks at menstruation (explains lack of clotting). Menstrual loss controlled by myometrial contractility, haemostatic plug formation & vasoconstriction.
How does cervical mucus vary?
Secreted by glands of cervix
o Early follicular phase: scant
o Late follicular phase: oestrogen induces increasing water content more stretchy
o Mid-cycle: just before ovulation - watery & easily penetrated by spermatozoa (fern-like pattern on microscope)
o After ovulation: progesterone from corpus luteum causes thick impermeable mucus (prevents entry of further spermatozoa).
Temperature and breast changes with cycle?
Basal body temp: Rise ~0.5°C following ovulation + sustained until onset of menstruation (thermogenic effect of progesterone at hypothalamic level). If conception occurs this is maintained throughout pregnancy (similar effect induced by administering progesterone).
Breast: Swelling in luteal phase (progesterone levels) – most likely due to vascular changes rather than glandular tissue. Oestrogen & progesterone act synergistically on the breast
What is primary amenorrhoea? Causes?
Failure to menstruate by age 16.
If secondary sexual characteristics absent, delayed puberty is most likely.
If normal pubertal development, suspect anatomical cause:
o Congenital absence of uterus (Mullerian ducts fail to develop)
o Imperforate hymen: haematocolpos – menstrual blood retained in vagina > cryptomenorrhoea (cyclical lower abdo pain) – treatment by incision
May also be a physiological (constitutional) delay (i.e. normal development but inherent delay in menstruation onset (often also delayed in mother). Progestogen challenge aids diagnosis: 5 days oral progestogen e.g. norethisterone > withdrawal should result in a PV bleed. Abdominal US may also be reassuring to confirm that uterus & ovaries are normal.
Low body weight + excessive exercise also associated with primary amenorrhoea.
What is secondary amenorrhoea?
General causes?
No menstruation for 6 months in absence of pregnancy. Most common causes are physiological (pregnancy, lactation, menopause). Weight loss, PCOS & hyperprolactinaemia are also common causes.
Causes
- Hypothalamic (weight loss, stress etc)
- Pituitary (hyperprolactinaemia, Sheehan’s)
- Ovarian (PCOS / premature ovarian failure / radio / chemo)
- Uterine / vaginal (hysterectomy, ablation, IUD)
- Other endocrine causes (rare: thyrotoxicosis, primary hypothyroidism, late-onset CAH)
What are hypothalamic causes of secondary amenorrhoea?
Weight loss, exercise, stress
Hypothalamic amenorrhoea (hypogonadotrophic hypogonadism) frequently associated with stress + will resolve spontaneously. Physical stress (heavy exercise) can suppress the HPO axis (↓ gonadotrophins, ↓ prolactin / oestrogen). If not related to low body weight, Tx depends on desire to conceive.
If no desire – oestrogen replacement therapy (COCP). If pregnancy desired: ovulation may be induced with pulsatile GnRH therapy or exogenous gonadotrophins.
Weight loss even only 10-15% below ideal may be associated with amenorrhoea. There may be a significant time interval between attaining ideal body weight and resumed ovarian activity. Ovulation induction therapy NOT recommended as pregnancy carries risk of growth restriction of fetus + increased perinatal mortality.
What are pituitary causes of secondary amenorrhoea?
Hyperprolactinaemia, Sheehan’s syndrome
Hyperprolactinaemia: Pituitary adenomas (microadenomas, macroadenomas) or secondary to other causes. Anterior pituitary produces prolactin (inhibited by dopamine from the hypothalamus).
Raised prolactin may be physiological (lactation) or pathological. This suppresses ovarian activity due to ↓ gonadotrophin secretion. Mild elevation common + may be stress related (e.g. venepuncture). Sustained higher levels > amenorrhoea + galactorrhoea (<50% with hyperprolactinaemia have galactorrhoea and <50% with galactorrhoea have hyperprolactinaemia).
What are ovarian causes of secondary amenorrhoea?
PCOS, premature ovarian failure, surgery / radiotherapy /chemotherapy)
PCOS = most common cause of anovulatory infertility, affects ~20% women UK. Diagnosis by 2 of 3 criteria: oligomenorrhoea / amenorrhoea, ultrasound of large-volume ovaries (>10cm³) and/or multiple small follicles (≥12 <10mm), clinical evidence of excess androgens (acne, hirsutism) or biochemical (raised testosterone). Recent evidence suggests underlying disorder of insulin resistance (dyslipidaemia & predisposition to non-insulin dependent diabetes & cardiovascular disease). COCP can regulate menses. Clomifene to induce ovulation with anovulatory infertility. If this fails, give gonadotrophin injections, or laparoscopic laser / diathermy to ovaries. Long-term: risk of endometrial hyperplasia & carcinoma (due to unopposed oestrogen stimulation of the endometrium).
Menopause (with cessation of ovarian function) usually occurs ~45-55 (early if <45 years). Premature ovarian failure (primary ovarian insufficiency) = cessation of ovarian function <40 years. Occurs in 1% of women. Like normal menopause, typically due to depletion of primordial follicles. May be idiopathic or caused by surgery, viral infections (e.g. mumps), cytotoxic drugs, radiotherapy or occasionally chromosomal abnormalities (XO mosaics or XXX). Poor prognostic signs for recovery = low oestrogen, high FSH & no menstrual activity. Pregnancy may be possible by IVF (donor oocytes). HRT: for symptoms & to minimise osteoporosis risk).
What are uterine / vaginal causes of secondary amenorrhoea?
Hysterectomy, endometrial ablation, progestogen IUD
Rarely, excessive uterine curettage (miscarriage, termination or secondary PPH) may remove basal layer of the endometrium & result in uterine adhesions (synechiae) –> Asherman syndrome. Treated by breaking down adhesions with hysteroscope +/- IUD.
How to manage secondary amenorrhoea?
Initial clinical management: exclude pregnancy, perimenopausal symptoms (e.g. flushing, vaginal dryness), weight changes, drugs, thyroid symptoms, examination (height, weight, visual fields, hirsutism / virilization, pelvic examination), serum (LH, FSH, prolacin, testosterone, thyroxine, TSH) + arrange TVUSS (PCOS).
If all results normal: consider mood disturbance, extreme exercise, Asherman syndrome + idiopathic amenorrhoea.
What is PCOS?
Aetiology / diagnostic criteria?
Complex endocrine disorder, symptoms + signs may vary from mild to severe & may vary over time.
6-7% prevalence, higher in women of South-Asian origin. 22-33% women have polycystic ovaries on USS.
Aetiology: unknown, likely multifactorial (genetic + environmental). THECA cells of ovary produce excess androgens. Decreased peripheral insulin sensitivity (insulin resistance) –> compensatory hyperinsulinaemia. Serum LH levels elevated in 40% women. May have increased serum oestrogen levels.
Rotterdam Diagnostic Criteria (2 out of 3):
- Oligo-anovulation or anovulation
o usually manifests as oligo/amenorrhoea - Clinical +/- biochemical signs of hyperandrogenism
o acne, hirsutism (Ferriman Gallwey scale), male pattern alopecia
o ↑ total or free testosterone / androgen - Polycystic ovaries (USS)
o large-volume ovaries (>10cm³) and/or multiple small follicles (≥12 <10mm)
Investigations for PCOS? Differentials?
Total testosterone, sex-hormone binding globulin (SHBG), free androgen index +/- pelvis USS
• Rule out other causes: LH + FSH, prolactin, TSH
DDx: simple obesity, primary hypothyroidism, premature ovarian failure, hyperprolactinaemia, non-classical congenital adrenal hyperplasia, Cushing’s syndrome, androgen-secreting neoplasm, hypogonadotrophic hypogonadism, high-dose exogenous androgens, acromegaly
What are long term complications of PCOS?
Long-term complications: • Impaired glucose tolerance & T2DM • Cardiovascular disease • Dyslipidaemia • Infertility • Sleep apnoea • Endometrial cancer • In pregnancy: higher rates of GD, pregnancy induced HTN, pre-eclampsia, pre-term delivery, SGA infants
How is PCOS managed? - broadly speaking
Counselling, manage oligo/amenorrhoea, manage hirsutism, manage anovulatory infertility
Counselling
• Inform women of long term complications
• Emphasise that being overweight makes condition worse > weight loss can result in spontaneous resumption of ovulation, improvement in fertility, increased SHBG, reduced basal level of insulin
• Advise measures to reduce CV risk
• Glucose Tolerance Test (GTT) for women with BMI >30, age >40 or strong FHx T2DM
How is oligo/amenorrhoea managed in PCOS?
- May lead to endometrial hyperplasia and later carcinoma
- Recommend treatment to induce withdrawal bleed at least every 3-4 months (Cyclical progestogens, COCP, Mirena IUS)
- If there is endometrial thickening (>10mm), should have endometrial sampling
How is hirsutism managed in PCOS?
Spironolactone: aldosterone + androgen receptor antagonist
Cyproterone acetate: progestogen with anti-androgen properties, combined with an oral contraceptive pill
Flutamide: androgen receptor antagonist
Orinthine decarboxylase inhibitor: limits cell division + function in pilosebaceous unit, available as a cream
How is anovulatory infertility managed in PCOS?
Weight loss if BMI >30
- Clomiphene citrate: inhibits hypothalamic oestrogen receptors inhibiting negative feedback of oestrogen on gonadotrophin release > upregulation of the HPG axis
- Gonadotrophins
- Ovarian drilling: destroy ovarian androgen producing tissue (40-50% reduction in total and free testosterone). Indirect modulating effect on pituitary, recruitment of new follicles & resumption of normal ovarian function
- Aromatase inhibitors: blocks oestrogen biosynthesis & reduces negative feedback at the pituitary
What is infertility? Subfertility?
How common?
Infertility: unable to conceive at all. Primary (couple have no previous pregnancies within relationship) or secondary (at least 1 pregnancy).
Subfertility: > 12 months without conceiving despite unprotected intercourse - lower chance per month of conceiving in a given months than normal (+/- 20% per cycle?).
NICE 2013: “A woman of reproductive age who has not conceived after 1 year of unprotected vaginal sexual intercourse, in the absence of any known cause of infertility, should be offered further clinical assessment + investigation along with her partner.”
Affects 1 in 6 couples (10-15% couples require advice or Tx): 3.5 million people. Impact on QoL similar to diagnosis of cancer.
