female reproductive system Flashcards
what are the important facts about female cycles
human ≃ 28-day cycle, but variable - mensturation
A single mature egg (oocyte) is released from paired ovaries each month
Endometrium (lining of uterus) is specially prepared for implantation of the ovum, should fertilization occur
If fertilization does NOT occur, endometrium degenerates and maturation of a new follicle resumes
Cycle repeats…….unless…………….
If fertilization DOES occur, conceptus in uterus secretes Human Chorionic Gonadotropin (hCG) which “rescues” corpus luteum (CL) and maintains Progesterone secretion
=> maintains endometrium
=> blocks Follicle Stimulating Hormone (FSH)/ Luteinising Hormone (LH) secretion and ‘new’ follicle growth
what is the function of uterus
Hosts the developing fetus
Produces vaginal and uterine secretions
Passes the anatomically male sperm through to the fallopian tubes
what does ovaries do
Produce the anatomically female egg cells.
Produce and secrete estrogen and progesterone
what is the role of estradiol
Estradiol
Before birth: released by the gonads in female fetus and leads to development of female reproductive organs
At puberty: estrogens levels rise and are responsible for sexual maturation and development of female secondary sex characteristics
Also involved in regulation of menstrual cycle and ovulation
what is the role of progesterone
Progesterone
Prepares the uterus for pregnancy
If pregnancy occurs: helps maintain the pregnancy; prepares the mammary glands for lactation
Oestrogen (E) Synthesis during
the Follicular Phase
LH stimulates the synthesis of androgens (from cholesterol) in theca cells
Some androgen diffuses to nearby granulosa cells of follicle
FSH stimulates the conversion of androgens into oestrogens in granulosa cells
(P450aromatase = CYP19)
Referred to as the “Two hormone / two cell mechanism” of oestradiol biosynthesis in the ovary
what is the ovarian cycle
Cycle has 3 phases:
Follicular phase
follicles mature, oocyte is prepared for release
Ovulation (at mid-cycle)
rupture of follicle and release of oocyte
Luteal phase
luteinization of ruptured follicle, preparation of reproductive tract for pregnancy, should fertilization occur
initated at puberty.. ends at menopause
Regulation of Hypothalamic-Pituitary-Ovary
(H-P-O) Axis
Gonadotropin-releasing hormone (GnRH) (tropic peptide hormone synthesized and released from GnRH neurons in hypothalamus) stimulates release of LH and/or FSH from the anterior pituitary
LH and FSH promote increased ovarian secretion of progesterone (P), androgen (A) and oestrogen (E)
P and E combined have a negative feedback effect on the pituitary and hypothalamus, inhibiting both LH and FSH secretion
During luteal phase:- both P and E high
=> LH and FSH low
Inhibin (peptide produced by follicle granulosa cells and corpus luteum) has selective negative feedback action on FSH secretion
Providing P is low, high level of E (as occurs at end of follicular phase) has positive feedback action on Hypothalamus & Pituitary to promote the preovulatory surge of LH
=> OVULATION
The Uterine or Endometrial Cycle
Proliferative Phase
Oestrogens (E):
increase thickness of endometrium
increase growth of endometrial glands and blood vessels
promote secretion of thin ‘sperm-friendly’ mucus
Secretory phase
Progestogen (P):
causes endometrial swelling and secretory development
increases blood supply
increases lipid and glycogen deposition
Menstruation
Caused by sudden decrease of E and P at end of luteal phase
Loss of hormonal stimulation initiates necrosis in the endometrium
Aided by uterine prostaglandins
Follicular Phase Menstrual Cycle
FSH rise at start of cycle stimulates growth of 6-12 small antral follicles
By Day 6 in cycle one follicle has been “selected”
Referred to as the “Dominant follicle”
This single follicle grows rapidly into a preovulatory (Graffian) follicle
Other secondary follicles not selected undergo atresia (degenerate)
Ovulation triggered by a surge of LH released from Anterior Pituitary
what is Ovulation (at Mid-cycle)
Ovulation occurs within 24h of pre-ovulatory LH surge
home ovulation detection kits detect this LH surge in urine!
LH surge causes swelling of follicle and thinning of wall
Oocyte (+surrounding cumulus cells) released into peritoneal cavity, where it is drawn into opening of fallopian tube (Fimbria)
Remainder of follicle (theca and granulosa cells) develops into corpus luteum (which lasts for ~14 days of “LUTEAL PHASE” of cycle”)
what is menopause
Depletion of finite ‘ovarian reserve’ by ~age 50 (UK mean age of menopause is 51)
Follicle development and ovulation ceases
Menstrual cyclicity decreases and eventually
ceases
Decreased production of ovarian hormones
(oestrogen, progesterone, androgen, inhibin)
Raised FSH and LH (due to lack of –ve feedback)
Diagnosed clinically after 12 months’ amenorrhoea
Premature ovarian failure (1% women <40)
what are symptoms of menopause
night sweats
mood swings
sleep disturbances
hot flushes
gas
Oestrogen Hormone
Replacement Therapy HRT
examples and use
Tablets (e.g.Elleste®), patches (e.g. Estradot®) or topical therapy via application of gel to the skin (e.g.Oestrogel®)- used to treat:
Hot flushes (sudden strong feelings of heat and sweating) (also termed vasomotor instability) and mood swings in peri-menopausal women
Vaginal dryness, itching, atrophy
(start with moisturisers and lubricants)
Prevention of osteoporosis in postmenopausal women (but not if this is the only symptom-use bisphosphonates instead)
what are the considerations with HRT?
Side effects include breast tenderness, headaches, vaginal bleeding
HRT increases the risk of venous thromboembolism, stroke, coronary heart disease and, after some years of use, endometrial cancer (reduced by a progestogen), breast cancer, ovarian cancer.
The minimum effective dose should be used for the shortest duration
Treatment should be reviewed at least annually
For osteoporosis alternative treatments should be considered (e.g. bisphosphonates)
For hot flushes and mood swings, antidepressants are sometimes used as an alternative (e.g. the SNRI venlafaxine) (off-label use)
Menopause-NICE (2019) recommendations for GPs
advices
contradictions
formulations
Menopausal women should be provided with information and advice on the stages of menopause, symptoms, lifestyle changes to manage symptoms, and risks and benefits of available treatments, to make an informed choice.
FSH test can be used to aid diagnosis e.g. in women under 40 or 40-45 with symptoms
Many women can manage symptoms with lifestyle changes e.g. regular exercise, avoiding triggers for hot flushes, ensuring good sleep hygiene.
Offer women HRT for menopausal symptoms after discussing risks and benefits.
For women unable or unwilling to use HRT:
For vasomotor symptoms — a trial of fluoxetine, citalopram or venlafaxine.
For vaginal dryness — a vaginal lubricant or moisturizer.
For psychological symptoms — self-help groups, psychotherapy, counselling, or antidepressants
Women who wish to try complementary therapies should be advised that the quality, purity, and constituents of these products may be unknown
Contraindications to HRT include:
Current, past, or suspected breast cancer
Oestrogen-sensitive cancer
Undiagnosed vaginal bleeding
Previous or current venous thromboembolism (deep vein thrombosis or pulmonary embolism), unless already on anticoagulants
Active or recent arterial thromboembolic disease (e.g. angina)
Untreated hypertension
Active liver disease with abnormal liver function tests
Formulation Choice
Transdermal patches/gel appropriate if:
Poor absorption (e.g. Crohns’ disease) or gastric side effects with oral route (tablets)
History of migraine-continuous plasma levels may be beneficial and with tablets there are greater fluctuations
Woman taking a hepatic enzyme inducing drug e.g. carbamazepine
Lactose intolerance-most tablets contain lactose
Poor symptom control on tablets
Low dose oestrogen intravaginal formulations suitable if only vaginal dryness symptoms-pessaries (Vagifem®), vaginal ring (Estring®), intravaginal cream (Ovestin®)
Formulations
-Women without a uterus: oestrogen only HRT, usually continuous
-Women with intact uterus: combined HRT (oestrogen and progestogen)
Combined HRT can be prescribed as:
Monthly cyclical regimens — oestrogen daily, progestogen at the end of the cycle for 10–14 days.
Three-monthly cyclical regimens — oestrogen daily and progestogen for 14 days every 13 weeks.
Continuous combined regimens — oestrogen and progestogen daily.
Formulations
Perimenopausal women:
Monthly or 3-monthly cyclical regimens may be used.
3-monthly regimen may be more suitable for women with infrequent periods or who are intolerant to progestogens.
Monthly regimen produces monthly bleeding; 3-monthly regimen produces a bleed every 3 months.
Continuous combined preps not suitable due to irregular bleeding
Postmenopausal women:
Monthly, 3-monthly cyclical regimens, or continuous combined regimens may be used.
Continuous regimens may be preferred as no withdrawal bleeding, but may produce irregular bleeding/spotting for the first 4–6 months
what is classed as Human Infertility
Failure to conceive after having regular unprotected sex for more than 12 months (or less, if you’re over 35)
Very common!
1 in 7 couples in UK have a problem establishing a pregnancy
Of these:
45% female problem (poor oocyte quality, ovulation failure, blocked/damaged tubes)
30% male problem (low sperm count or quality)
25% undiagnosed
what is initial advice for women for infertility
INITIAL ADVICE FOR WOMEN
Drink no more than 1 or 2 units of alcohol once or twice a week and avoid intoxication to reduce the risk of harming a developing fetus
Smoking and passive smoking is likely to reduce fertility; refer to smoking cessation programmes
Women with BMI ˃30 take longer to conceive; losing weight increases the chance of conception
Women with BMI <19 with irregular or no menstruation should increase body weight to improve their chance of conception.
“FERTILITY DRUGS” are given to women to increase their chances of achieving pregnancy (through natural intercourse or Assisted Reproductive Technology (ART) e.g. using In-Vitro Fertilisation (IVF) + embryo transfer)
what are Gonadotrophins
side effect
FSH + LH combined (1:1 ratio) - menotrophin (e.g. Merional®, Menopur®) purified from urine of post-menopausal women
FSH (recombinant human) (follitropin alfa, follitropin delta)
LH (recombinant human) - lutropin alfa
LH-like: -recombinant human chorionic gonadotrophin, r-hCG (Ovitrelle® - produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology)
Both LH and FSH used for:
Treatment of infertility in women with proven hypopituitarism (or have not responded to clomiphene)
To induce multiple follicle development (superovulation) for assisted conception (i.e. IVF) (follitropin delta and lutropin alfa are licensed for this)
[FSH to induce multiple follicle growth -> LH for final maturation]
Side effects
Gastrointestinal discomfort; headache; nausea; ovarian and fallopian tube disorders; pelvic pain; uterine pain.
Uncommon: Breast abnormalities; diarrhoea; dizziness; fatigue; hot flush; vomiting
Rare: Skin reactions; thromboembolism.
what are Gonadotrophins
side effect
FSH + LH combined (1:1 ratio) - menotrophin (e.g. Merional®, Menopur®) purified from urine of post-menopausal women
FSH (recombinant human) (follitropin alfa, follitropin delta)
LH (recombinant human) - lutropin alfa
LH-like: -recombinant human chorionic gonadotrophin, r-hCG (Ovitrelle® - produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology)
Both LH and FSH used for:
Treatment of infertility in women with proven hypopituitarism (or have not responded to clomiphene)
To induce multiple follicle development (superovulation) for assisted conception (i.e. IVF) (follitropin delta and lutropin alfa are licensed for this)
[FSH to induce multiple follicle growth -> LH for final maturation]
Side effects
Gastrointestinal discomfort; headache; nausea; ovarian and fallopian tube disorders; pelvic pain; uterine pain.
Uncommon: Breast abnormalities; diarrhoea; dizziness; fatigue; hot flush; vomiting
Rare: Skin reactions; thromboembolism.
what is Clomiphene citrate (Clomid)
side effect
drug class
anti-oestrogens
Clomiphene citrate (Clomid) used in treatment of female infertility only for patients in whom ovulatory dysfunction is demonstrated e.g. women with Polycystic Ovary Syndrome (PCOS)
Side effects: mood swings; hot flashes; abdominal discomfort;
nausea
what is leterzole
what does it do?
Letrozole (licensed for breast cancer) is sometimes used ‘off-label’
induce FSH/LH release by binding to oestrogen receptors in hypothalamus, thus interfering with negatuve feedback mechanism stimulates increased output of pituitary gonadotrophins, which stimulates the maturation and endocrine activity of ovarian follicle
Chorionic gonadotrophin (hCG) sometimes used as adjunct
Risk of multiple pregnancy (6.9% of pregnancies are twins, 0.5% triplets, 0.3% quadruplets, 0.13% quintuplets)
Classification of ovulatory disorders and how to deal with it
The World Health Organization (WHO) classifies ovulation disorders into 3 groups.
Group I: hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism)
Group II: hypothalamic-pituitary-ovarian dysfunction (predominately polycystic ovary syndrome (PCOS))
Group III: ovarian failure
Group 1 hypothalamic pituitary failure
Improve chance of ovulation and pregnancy by increasing BMI to ˃19 if BMI is low and reducing exercise if high levels
Offer pulsatile administration of gonadotrophin-releasing hormone or gonadotrophins with LH activity to induce ovulation
Group 2 hypothalamic-pituitary-ovarian dysfunction
Advise those with a BMI of 30 or over to lose weight- this alone may restore ovulation, improve response to ovulation induction agents and have a positive impact on pregnancy outcomes
Use clomifene citrate or metformin or both
For 2nd line, try gonadotrophins or laparoscopic ovarian drilling
what are Anti-Fertility Drugs”
GnRH antagonists (cetrorelix, ganirelix)
inhibit LH/FSH release from Anterior Pituitary (AP)
inhibit follicle development
iinhibit ovarian steroid output
used in IVF treatment cycles -suppression of endogenous gonadotrophins before giving exogenous FSH/LH
Oral contraceptive pills (synthetic oestrogen and progesterone derivatives)
inhibit follicle development and ovulation
exert negative feedback on Hypothalamus-Anterior Pituitary
what MENORRHAGIA
treatment
MENORRHAGIA
Regular, heavy & prolonged periods - due to increased uterine vasodilation and reduced haemostasis associated with increased PGE2, PGI2 and prostacyclin
Treatments:
Intra-Uterine System (IUS)(e.g. Mirena® coil-levonorgestrel 20 mcg/24hrs LNG-IUS)
Combined oral contraceptive (COC) pill or progestogen only pill
NSAIDs
Antifibrinolytic (tranexamic acid)
Hysterectomy
what is PRIMARY DYSMENORRHOEA
treatment
PRIMARY DYSMENORRHOEA
Painful periods with uterine cramps associated with increased uterine PGE2, PGF2a
Treatments:
NSAIDs and/or hormonal contraceptives e.g. COC /progestogen pill, LNG-IUS
Endometriosis
treatment
Endometrial tissue growing outside uterus (e.g. on ovary, bowel, bladder) under hormonal control; painful!
Incidence: 5-10% of women
Chronic disease (throughout reproductive life)
Treatment:
Pain relief-paracetamol, NSAIDS
COCs or progestogen only pill-most women are controlled with this
Surgery probably most effective-laparoscopy or hysterectomy
After laparoscopy, consider COC to prolong surgical benefit
As an adjunct to surgery for deep endometriosis involving bowel, bladder or ureter, consider 3 months of GnRH agonists (these initially stimulate, then reduce FSH/ LH, and reduce oestrogen and androgen production). Licensed preparations include goserelin (SC inj), leuprorelin (SC/IM inj) nafarelin and buserelin (nasal sprays)
Ovarian Androgen Excess
if ovaries produce excess androgen woman may develop male characteristics (hirsutism, deepening voice, changing body contour). Imbalance may be caused by ovarian tumour (e.g. thecoma) or polycystic ovarian syndrome (PCOS).
PCOS (polycystic ovarian syndrome)
treatment
Affects 5-10% of women of reproductive age
Abnormal follicle development, LH/FSH ratio altered –>
Many small antral follicles –> androgen excess ->
Hirsutism, acne, anovulation or irregular cycles etc ..
Strong association with insulin resistance and obesity
Treatments:
Diet modification/weight loss
Insulin-sensitizing drugs (e.g. metformin)
Clomiphene, FSH (for infertility)
Anti-androgens for hair growth (e.g. particular types of combined oral contraceptive tablets (such as co-cyprindiol, Dianette, Marvelon and Yasmin), flutamide, cyproterone acetate, finasteride, spironolactone)
Uterine Fibroids
Benign tumours in muscle layer of uterus (myometrium) - most common, benign tumours in women of childbearing age
Common-1 in 3 women have them at some point
More common in women of African-Caribbean origin,30-50 age, obesity
Pea size to melon size!
May be asymptomatic or cause heavy or painful periods, abdominal pain, pelvic ‘fullness’, frequent urination, pain during sex (dyspareunia)
Treatment:
mild
NSAIDs, COC, progestogen only pill, LNG-IUS
debilitating
GnRH agonists e.g. goserelin (stop ovaries producing oestrogen and can shrink fibroids)
endometrial ablation to remove uterus lining
surgery to remove fibroids or hysterectomy
low sex drive
Vaginismus
Dyspareunia
Low sex drive (libido) – due to low oestrogen and/or androgen levels?
Steroid supplementation may be beneficial- esp. in menopausal women- HRT can help e.g. Tibolone (Livial®) oestrogenic, progestogenic and androgenic activity
Investigate and treat cause e.g. depression, diabetes, underactive thyroid, taking antipsychotics/antidepressants
Vaginismus - spasmodic involuntary muscle contraction of vaginal wall prevents intromission –
usually psychological in origin (so cognitive therapy used)
Dyspareunia – difficult and/or painful intercourse
(e.g. due to vaginismus, vaginal dryness, vaginitis)
* Vaginal lubricants and topical oestrogens useful - esp. after menopause
