HUMAN REPRODUCTION

CONTRACEPTION Background o Contraceptive Effectiveness Method Failure: inherent risk of failure provide the method is used correctly User Failure: occurs when a given method is not used correctly Measured by the Pearl Index: failure rate per 100 women years Failure rate = (Total accidental pregnancies x 1200) / (Total months exposure) Chance Calendar Ovulation Monitoring Withdrawal Male Condom Female Condom Diaphragm Combined OCP Progesterone Only Pill Depot Progesterone IUCD Mirina Coil Tubal Ligation Vasectomy o Types of Contraception Reversible Hormonal Methods Intrauterine Devices Barrier methods Natural Methods Permanent Male Sterilization Female Sterilization Emergency Oestrogens only Oestrogen/Progestin Combination Progestin only IUCD Hormonal Contraception o OCP Composition of Pills Contains oestrogen and progesterone o The oestrogen is ethinylestradiol (EE): 20-50g o The progestogens are in 2 groups 2nd generation: levonorgestrel, norethisterone 3rd generation: gestodene, desogestrel Taken for 3 out of every 4 weeks 1 85 9 1 1 3 5 6 0.1 3 0.3 0.6 0.09 0.4 0.1

Ex: Logynon 6 pills w/ 50g Levo + 30g EE, 5 pills w/ 75g Levo + 40g EE and 10 pills w/ 125g Levo + 30gEE

Mode of Action Thickens cervical mucus Creates endometrial hostility Reduces tubal motility Ovulation suppression o Decreased frequency of GnRH pulses o Inhibits LH surge Pharmacology After ingestion 80-90% of the progestogens available in the upper small bowel Estrogens undergo 1st pass metabolism by conjugation w/ sulphate in the gut wall After absorption, estrogen and progestogens carried to the liver and metabolised. Conjugates re-enter the bowel, the bowel flora remove the glucuronides and restores some EE for reabsorption The reasborbed progestogens is inactive Drug Interactions Induction of liver enzymes increases metabolism and elimination of EE and progestogens in the bile o Broad spectrum antibiotics disturb gut flora and reduce EE reabsorption o Anticonvulsants are enzyme inducers. May be >4 weeks before the liver returns to normal after an enzyme inducer The options are to increase dose or reduce the pill free interval from 7 to 4 days Advantages of OCP Contraceptive o Highly Effective o Highly convenient o Reversible Non-Contraceptive o Improved dysmenorrhoea, DUB, premenstrual symptoms Combination of progestin and oestrogen stabilises endometrium, decreased prostaglandin content of menstrual fluid, decreases local endometrial vasoconstriction & myometrial contractility o Ovarian/endometrial carcinoma Endometrial Cancer 50% decreased risk overall Related to duration of OCP use Benefit persists up to 20 years after stopping OCP Ovarian Cancer 40-80% decreased risk overall Related to duration of OCP use Benefit persists up to15-20 years after stopping OCP o Less benign breast disease: 30-50% risk of fibrocystic disease o Less ovarian cysts: Dose-dependent decrease in benign ovarian cysts o Less PID Decreased risk salpingitis 50-80% Because of thickening of mucus Because of decreased retrograde menses No protection against lower genital tract infections / STDs 2

chlamydia & gonorrhoea o Ectopic Pregnancy (significant reduction) o Acne: 50% decrease in acne symptoms Similar response rate to topical therapy or systemic antibiotics o Colorectal Cancer: Some evidence supports protective effect, up to 50% o Bone density: Stable or slight increase in bone density Disadvantages of OCP Circulatory o Risk of thrombotic disease: VTE, MI, CVA o Hypertention Liver disease o Adenoma/carcinoma o Jaundice o Gallstones Side Effects Breakthrough bleeding, nausea, breast tenderness Lower dose OCPs have less side-effects, but also: o Effectiveness 95-97% o Poorer cycle control (breakthrough bleeding more common) o Less margin for error if pills missed Major Complications Venous thromboembolism o Three-fold increase in risk o Gestodene & desogestrel have 7-fold increase risk o Overall risk low: 3.0 vs. 9.6 vs. 21.1 per 100,000 users annually o Mortality low, but does increases with age o Factor V Leiden mutation identification unhelpful Stroke o Haemorrhagic: No relation to OCP use in absence of risk factors Cigarette smoking (x3) & hypertension (x5-9) o Thrombotic / ischaemic: 2.5 fold increased risk But overall risk low: 1 vs. 2.5 per 100,000 users per year Highly related to age, SMOKING, MIGRAINE, oestrogen dose Therefore it is vital to check patients BP Breast Cancer: o Meta-analysis in 1996: Current users had increased risk of 1.24 Unrelated to duration, dose, family history This increased risk persists for about 10 years, then disappeared These cancers tend to be more localised Unclear if this increase is real (promotional effect of OCP on tumour) or if it is a detection bias appearing because of increased surveillance of such patients Myocardial infarction: o Some in women with risk factors: Age, smoking, DM, hypertension o Nonsmokers without DM & with regular BP checks have no increase in risk of MI while taking OCP 3

Prescribing the OCP Aim: to achieve good cycle contraception and good cycle control with as low a dose oestrogen and progestogen as possible The OCP is usually started on the 1st day of the period Most pills contain 21 active tablets then a 7 day pill free interval Some packets are available where there is a placebo for the 7 to substitute for the pill free interval Some packets have 2 or 3 different ratios of oestrogen and progestogen. Thes biphasic or tri-phasic tablets aim to mimic the natural cycle Missed Pills 7 Day Rule o 7 Consecutive pills are enough to inhibit ovulation o 7 Pills can be omitted w/o ovulation o >7 Missed pills risk of ovulation

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Contraindications to the OCP Previous VTE Cardiomyopathy/ previous MI/ prosthetic heart valve Lipid disorders TIA/ CVA Active liver disease Porphyria Any condition affected by sex steroids Pregnancy Undiagnosed vaginal bleeding

o Nuvaring: Vaginal Ring Ethinylestradiol + etongestrel Ring inserted for 3 weeks, then 1 week free 4

8% failure rate in 1st year of use

o Ortho Evra: the Patch Combined oestrogen and progestogen: ethinyl estradiol and norelgestromin 3 one week patches followed by one week free Same S/E of OCP 8% failure rate in first year of use

o Progesterone only pill Noriday= Norethisterone 350 mcg Various effect on the ovarian function Ovulation Cervical mucus: reduce sperm permeability (max effect 4hrs after dose) Endometrium: reduced blastocyst receptivity Missed Pills: extra precautions if > 3hrs late, for 7 days Enzyme inducers reduce POP levels Advantages Efficacy No in malignancy No estrogen SEs Minimal effect on lactation Disadvantages Timing Altered mentruation Functional ovarian cysts Contraindications to POP Undiagnosed vaginal bleeding Pregnancy Previous Ectopic Sex steroid dependent cancer Liver Disorders o Depot Injection (eg Depot Provera) Depot medroxyprogesterone acetate 150mg every 12 weeks Highly effective: Equivalent efficacy to OCP + TL combined! 150 mg intramuscularly gives effective contraception for 13 weeks o Mechanism of action is by inhibtion of ovulation, cervical mucus thickening, and creation of atrophic endometrium Repeat injection every 3 months Given up to Day 5 of cycle Suitable for women on enzyme inducers but shorten the interval 8-10 weeks Advantages Effective contraceptive Convenient Less PV bleed Less Dysmenorrhea 5

Less ovarian cyst Protects against endometrial carcinoma Disadvantages Cant be removed Menstrual problems Loss of bone density Delay in fertility return Depression, headaches

o Progestogen Implants Norplant: 6 plastic rods containing 36mg levonorgestrel 5 years effective contraception Equivalent efficacy to tubal ligation Implanton: releases 40g etonogestrel daily Lasts 3 years Inhibits ovulation, alters cervical mucus Advantages: Longevity, does not interfere with lactation, prompt return to fertility on removal Disadvantages: Needs special expertise for insertion & removal Irregular/breakthrough bleeding during 1st 2-3 years May have small amount weight gain, headaches & acne

o Intrauterine Devices Copper IUCD T-shaped copper-containing device placed within endometrial cavity Mechanism of action by inhibiting sperm migration and ovum transport Largely superseded by Mirena in Europe Radioopaque on x-ray Best to insert at time of menses o Pregnancy unlikely o Technically easier as cervix already open Disadvantages: o Risk of perforation, PID at insertion Does not have any subsequent risk of spontaneous pelvic infection, unless patient separately contracts an STD o Menorrhagia: Mean blood loss increases from 30 to 60-80ml per day o Ectopic Pregnancy if IUCD Fails IUCD does not cause ectopic pregnancy IUCD effectively protects against all forms of pregnancy However, if IUCD fails and pregnancy occurs, there is an risk that it will implant in fallopian tube, resulting in ectopic pregnancy Contraindicated in rheumatic heart disease Mirina Coil Contains 52mg levonorgestrel and releases 20 g / 24 hours Advantages o Very effective contraception: Pearl index only 0.09 / 1,000 women years o Last for 5 years o Significant reduction in mean menstrual blood loss 6

 86% have reduced bleeding by 3 months 92% by 6 months 97% by 12 months o Low rate of ectopic pregnancy: 0.02 / 1,000 women per year o Less dyemenorrhoea o Rapid return of fertility Barrier Contraception o Mode of action: Block the passage of sperm from the male to the oocyte o Advantages: reversibility and minimal side effects o Disadvantage: efficacy depends on quality of use o Failure rates are low if used consistently by well motivated couples o Types Male Condom(Latex) Failure rate 3-16% Protect against STDs Female Condom Polyurethane sheath attached to a ring which sits at the vaginal entrance Protects against STDs Failure rates 5-20% Cervical Caps & the Female Diaphragm Soft latex dome attached to a ring placed in the vagina between symphysis pubis and the posterior vaginal fornix Little contraceptive effect alone: designed to hold spermicidal cream in contact with cervical mucus Must be placed in the vagina before genital contact and should remain in place for a 6 hours after The user needs to be taught how to insert and remove it correctly Women need to have a diaphragm correctly fitted as the size can change after childbirth Less reliable than IUCD Natural Contraception o Periodic Abstinence Natural Family Planning Does not involve the use of pharmacological or mechanical agents Requires restriction of intercourse to those days during the menstrual cycle on which conception is least likely to occur Fertile period: 6 days before and 2 days after ovulation o Cervical mucus clear and watery, easily stretched into stands Spinnbarkeit o Mid-cycle rise in core body temperature at time of ovulation Non-fertile: 3 days after until 7d before ovulation, cervical mucus is viscous Failure rates 20%: but improves in well motivated couples Emergency Contraception o Postcoital Contraception (eg morning after contraception) Can be used after: Unprotected intercourse After accidents with a barrier method If one or more combined pill has been missed at the beginning or the end of a

packet Must be administered within 72 hours after unprotected inetrcourse Method of action Depends on when administered Pre ovulation: o Disruption of follicular growth, development, maturation o Leads to anovulation or delayed ovulation o Altered hormone production during luteal phase Post ovulation: o Inflammatory effect on endometrium No effect on ongoing pregnancy Types: Oestrogens only Oestrogen/Progestin Combination: traditional agents o 200g ethinylestradiol + 2mg levonorgestrel o 12-hourly x 2 doses o 30% incidence of nausea o Failure rate 2-3% Progestin only: main agents used in Ireland o Levonorgestrel 0.75mg o 12-hourly x 2 doses o Less side-effects o Similarly effective IUCD o Copper-containing IUCD o Can be used up to 7 days after intercourse o Failure rate < 0.1% o Uncertain mechanism of action Alters tubal motility Inflammatory effect of copper on implantation

Sterilization o Male: Vasectomy Intended as permanent / irreversible procedure Minor surgical procedure w/ local anaesthetic Extraperitoneal/trans-scrotal ligation of both vas deferens Serious morbidity and death very rare Minor complications (50%): Scrotal swelling, bruising, pain Haematoma (2%) Infection (2%) Long term: chronic testicular pain Failure Rate: 1/2000 Disadvantage: Delayed efficacy as requires at least 2 semen analyses at 12 and 16 weeks confirming azospermia before success proven No increased risk of testicular cancer or heart disease Reversal Not designed to be reversible 10% request reversal but 40% success rate May be technically feasible but because of the development of auto antibodies 8

against sequestered sperms fertility may not be restored o Female: Tubal Occlusion Mini-Laparotomy at time of C-section = Pomeroy technique Laparoscopy w/ Filshie clips Daycase procedure: requires general anaesthetic A laparoscopy is performed and a Filshie clip is applied to the mid-portion of each fallopian tube Associated with the all the risks of laparoscopy: o Anaesthetic: respiratory, vaso-vagal,co2 o Bowel perforation (0.4%): laparotomy o Blood vessel perforation (0.002%) : laparotomy o Bladder perforation o Bleeding/ Infection at port sites o Gas embolism o Port site hernia Timing of Procedure o Should be performed an appropriate interval after pregnancy o Post-partum or post-termination tubal occlusion has increased failure rates o Can be performed at anytime during menstrual cycle provided that the woman is using contraception right up to the day of surgery and continues using contraception until next menses o Pregnancy test performed on the day of procedure but cant exclude luteal phase pregnancy Failure Rate Lifetime failure rate 1 in 200 Failure can occur several years after the procedure If fails, increased chance pregnancy is an ectopic If have any irregular bleeding or think they might be pregnant: should seek early medical advice Counselling Inform women of the alternative options available and the risk and benefits of alternative contraception Verbal advice should be supported with written advice on tubal ligation, should be given to and taken away by patient Advise women with increased risk factors (obesity, previous abdominal surgery) of the possibility of laparotomy Special considerations for women < 30yrs and women with no children Decision regarding tubal ligation at the time of caesarean section such be decided early in pregnancy Not associated with an increased risk of menorrhagia Reversal Procedure intended to be permanent Low success rates with reversal

AMENORRHEA Definition o Primary Amenorrhoea: absence of onset of menses by age 14 in absence of development of secondary sexual characteristics or by age 16 in presence of normal growth and secondary sexual characteristics o Secondary Amenorrhea: absence of menstruation for a length of time equivalent to a total of at least 3 of the previous cycle intervals, or 6 months of amenorrhea, in a woman who has been menstruating Causes o General: anything the interferes w/ normal sequence which culminates in menstruation o Pregnancy is most common cause o Hypothalamic dysfunction (hypogonadotropic hypogonadism): Suppression of GnRH pulsatile secretion which can be caused by: Stress Corticotropin-releasing hormone (CRH) which directly inhibits hypothalamic GnRH secretion Weight loss especially anorexia Excessive exercise Severe emotional stress Chronic disease Kallmanns syndrome: Amenorrhea with anosmia, caused by mutation of Xp CNS tumour o Pituitary dysfunction (Hypogonadotropic, hypogonadism): Pituitary adenoma (usually prolactinoma) 20% of cases of secondary amenorrhoea Prolactin decreases GnRH secretion Symptoms: Amenorrhoea and galactorrhoea May have visual field defects Hypothyroidism Lesions compressing the pituitary stalk causing interference with delivery of hypothalamic GnRH Other pituitary tumours such as craniopharyngiomas Pituitary infarction/Sheehans syndrome: Acute necrosis of pituitary gland due to PPH o Premature ovarian faliure (Hypergonadotropic hypogonadism): Defined as ovarian faliure at age < 40 years, due to early depletion of ovarian follicles Causes: Idiopathic Autoimmune disorders Infection eg mumps Irradiation or chemotherapy High serum FSH due to loss of negative feedback from oestradiol o Chronic anovualtion due to increased androgens: Cushings syndrome Congenital adrenal hyperplasia Polycystic ovarian syndrome 20% of cases of secondary amenorrhoea Diagnosis: 2/3 of following required 10

o 1) Hyperandrogenism clinical or biochemical o 2) Amenorrhoea or oligomenorrhoea o 3) Polycystic ovaries on ultrasound o Disorders of the uterus or outflow tract Mullerian anomalies (Rokitansky- Kuster- Hauser syndrome): vaginal agenesis Absence of uterus in a phenotypic female but genotypic male (Testicular feminization syndrome) Imperforate hymen Endometrial atrophy secondary to prolonged progesterone administration Ashermanns Syndrome: endometrial scarring following vigorous currettage or infection Infection: TB or IUCD related infection

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o Diagnosis o Rule out pregnancy in all patients o History: Primary or secondary amenorrhoea Recent stress/weight loss or gain Acne/hirsuitism Headache/visual field defects pituitary tumour Polyuria/polydypsia Symptoms of oestrogen deficiency Medications eg antipsychotics o Physical Examination 11

o Investigations FSH/LH Prolactin TFTs Testosterone/DHEAS

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o Treatment o Treat the underlying cause o If anovulatory, need to give periodic progesterone to prevent endometrial hyperplasia o Hypoestrogenic anovulation: need to induce oestrogen production or give oestrogen to prevent bone loss. Need to make sure patient also has progesterone so they dont have Unopposed estrogen o Post-pill amenorrhea. Needs to be investigated if has been 6 months since discontinuing OCP or 12 months since last injection of Depo-provera It is not medically crucial for the woman to have a period once a month

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HIRSUTISM Defintion: excessive male pattern hair growth in women o Virulizaiton Masculinisation Severe hirsutism Rapid onset & progression Male pattern balding Deep voice Clitromegaly Progression: stable course w/ slow progression Scoring System: Ferriman and Gallwey o 9 Sites: each scored 1-4 for minimal to heavy growth Upper lip Chin Mild upper arm Breast Mild abdomen Upper back Lower back Lower abdomen Cause: hyperandrogenism o Ideopathic Abnormally high androgen metabolism in skin Dihydrotesterone is high due to increased 5-reductase in skin Circulating androgen levels are normal Familial especially in Mediterranean descent o Ovarian PCOS Starts soon after menarche and is progressive Likely due to relative insulin resistance Features o Menstrual irregularities ( Amenorrhea/ Oligomenorrhea) o Anovulatory cycles o Infertility QuickTime and a TIFF (Uncompressed) decompressor o Elevated serum LH, LH:FSH ratio is often >3:1 are needed to see this picture. o Hyperinsulinaemia Diagnosis: 2 out of the following 3 criteria must be met: o Oligomenorrhoea or Amenorrhoea o Ultrasound evidence of polycystic ovaries: string of pearls sign o Physical or biochemical evidence of hyperandrogenism Androgen producing tumours (virilization common), serum testosterone levels >200ng/dl Sertoli-Leyding cell tumour Hilus cell tumour (generally in post-menopausal women) Lipoid-cell tumour 13

o Adrenal Congenital adrenal hyperplasia (deficiency in 21-Hydroxylase enzyme) Androgen producing adrenal tumours Cushings syndrome: Central obesity, thin skin, facial flushing, HT & easy bruising o Drugs Danzol Steriods Diazoxide Evaluation o Complete history and physical examination o Laboratory tests: Serum dehydroepiandrosterone sulfate (DHEAS) Serum testosterone (total and free) 17-Hydroxyprogesterone (17-OHP) to rule out congenital adrenal hyperplasia Treatment: Underlying Cause o PCOS Several treatment options, choice of which depend on patients goals Many manifestations of PCOS are improved by weight loss OCP containing an anti-androgen (eg Dianette) or minimally androgenic progesterone Improves hirsuitism and acne Prevents endometrial hyperplasia Infertility Due to anovulation Weight loss and lifestyle modifications important Ovulation induction with clomiphene and metformin 80% success

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PATHOPHYSIOLOGY OF INFERTILITY Definition: involuntary failure to conceive within 12 months of commencing unprotected intercourse o Primary Infertility: couple has never conceived o Secondary Infertility: couple has had at least one previous conception o Fecundity: the ability to reproduce Incidence o Infertility is common, affecting approx. 12% of couples o 85 90% of couples will conceive within 12 months of regular, unprotected intercourse Etiology o Male and Female causes: 20 40% of couples will have multiple causes Male Factors 20 25% Anovulation 15 20% Tubal 15 40% Endometriosis 5 10% Unexplained 20 30% Male Fertility o Testicular Function: Spermatogenesis: occurs in the seminiferous tubules Steroidogenesis: Testosterone is produced by the interstitial cells of Leydig o Under the control of the Hypothalamic-Pituitary axis GnRH secreted by the Hypothalamus acts on the Pituitary secretion of FSH and LH FSH stimulates spermatogenesis LH acts on the interstitial cells of Leydig to enhance testosterone synthesis

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o Effects of Testosterone Regulation of gonadotrophin secretion by the hypothalamic-pituitary system Initiation and maintenance of spermatogenesis 15

 Formation of the male phenotype during embryogenesis Promotion of sexual maturation at puberty o Causes of Male Infertility Hypothalamic/Pituitary disease (Hypogonadotrophic Hypogonadism) 1-2% Deficiency of GnRH or Gonadotrophins (FSH and LH) May be congenital or acquired Congenital o Kallmanns Syndrome: Defect in GnRH secretion associated with anosmia o Associated with other genetic syndromes eg. Prader-Willi Syndrome, Laurence-Moon-Biedl Syndrome Acquired o Pituitary Disease Pituitary Adenomas eg. Prolactinoma Surgery/ Radiotherapy Vascular lesions eg. Pituitary infarction Infiltrative lesions eg. Sarcoidosis, TB o Negative feedback due to excess androgen (eg. anabolic steroid use) or excess estrogens (eg. estrogen producing tumour) o Obesity o Serious systemic illness Testicular disease = Primary Hypogonadism 30-40% Congenital: Klinefelters Syndrome 46XXY Cryptorchidism: Failure of testicular descent Varicocoele: Dilatation of the scrotal venous plexus, a/w poor semen quality Infections: Mumps orchitis Radiation Drugs: o Alkylating drug (cyclophosphamide,chlorambucil). o Antiandrogens (cyproterone, spironolactone), o Ketoconazole o Cimetidine Smoking: Men who smoke cigarettes are more likely to have low sperm counts Hyperthermia: Prolonged high testicular temperature leads to impaired spermatogenesis Anti-sperm antibodies Post-testicular defects (disorders of sperm transport) 10-20% Genital Tract Obstruction o Post-vasectomy o Congenital absence of vas deferens: may be associated with cystic fibrosis o Infection: N gonorrhea, chlamydia, TB Defective Ejaculation o Erectile dysfunction: 2 to neurological disease, Psychosexual, Drugs o Retrograde ejaculation o Ejaculatory failure Unexplained 40-50%

Fertility in the Female o Physiological Control of Fertility 16

Ovulation is under the control of the Hypothalamic-Pituitary system GnRH released from the hypothalamus stimulates secretion of FSH and LH from the pituitary gland. FSH promotes follicular development in the ovary LH is critical for ovulation and maintenance of the corpus luteum Cyclical changes in GnRH, FSH and LH release control the menstrual cycle Menstrual Cycle Follicular Phase: o GnRH pulse frequency increase in FSH development of follicles o Serum estradiol concentrations proliferation of uterine endometrium Midcycle: o Serum estradiol concentrations continue to rise until they reach a peak approximately one day before ovulation o Switch from negative feedback control of gonadotrophin secretion by ovarian hormones to positive feedback leads to surge in LH levels o LH surge ovulation: Dominant follicle ruptures releasing the oocyte Luteal Phase: o Ruptured follicle becomes corpus luteum which secretes progesterone and estradiol o Gradually increasing progesterone levels during the luteal phase leads to further development and organization of the endometrium o If fertilization occurs the corpus luteum is maintained and progesterone levels remain elevated o In the absence of fertilization levels of estradiol and progesterone fall, FSH levels rise and a new cycle begins

o Etiology of Female Infertility Ovulatory disorders 25% Hypothalamic-Pituitary Failure: Hypogonadotrophic Hypogonadism o Low FSH,LH o Causes: Kallmanns Syndrome Excessive weight loss/Stress Hypothalamic-Pituitary Dysfunction o Normal FSH, LH o PCOS Ovarian Failure: o Elevated FSH, LH o Genetic: Turner Syndrome (45XO) o Premature Ovarian failure o Radiotherapy o Chemotherapy o Autoimmune Diseases Endometriosis - 15% Definition: Presence of endometrial tissue outside the uterine cavity Affects 2-3% of women Seen in 10-20% of women undergoing investigation for inferility Mechanisms of Impaired Fertility: o Anatomic distortion from pelvic adhesions o Damage to ovarian tissue by endometrioma formation and removal 17

o Production of cytokines which impair the normal processes of ovulation, fertilization, and implantation Tubal blockage and other tubal abnormalities Infection: o PID caused by organisms such as Chlamydia and Gonorrhoea o Pelvic TB Surgery: Abdominal or Pelvic surgery leading to pelvic adhesion formation Congenital Anomalies Hyperprolactinemia Causes: Pituitary Adenomas Secondary to: o Hypothyroidism o Chronic Renal Failure o Drugs Suppresses ovarian activity by interfering with secretion of gonadotrophins Unexplained In 20-30% of couples undergoing investigations for infertility routine investigations will yield normal results Possible causes of infertility in these couples include: o Luteal-phase deficiency: Abnormalities of corpus luteum resulting in reduced progesterone levels o Failure of rupture of the dominant follicle o Mild endometriosis o Occult infection o Immunological causes o Psychological causes

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INVESTIGATION & TREATMENT OF INFERTILITY Initial Assessment o Often carried out by the general practitioner o Counselling can be provided and preliminary tests performed o Majority of couples will then be referred to a specialist clinic for further investigation o Ideally the couple should be seen together o General Advice Smoking: Advise both partners to stop Alcohol: Advise both partners to limit alcohol intake Weight loss: Advise female to lose weight if BMI > 30 Temperature: Advise men to wear lose-fitting underwear o Note: infertility if a diagnosis of exclusion History o Female Age Previous conception Duration of infertility Previous contraceptive use Menstrual History: Cycle length, regularity, menorrhagia, dysmenorrhoea, IMB, PCB Previous sexually transmitted infections Previous surgery especially abdominal or pelvic Smoking Drug use o Male Age Previous evidence of fertility Previous sexually transmitted infection History of mumps Testicular maldescent Occupational exposure to chemicals, radiation Smoking Drug use o Couple should also be asked about coital frequency/difficulty with coitus Examination o Female General: Height/Weight/BMI Blood Pressure Hair distribution, presence of acne Abdomen: Masses or tenderness Pelvis: Assess normality of external genitalia/ state of hymen Assess vagina and cervix Record size, position, mobility of uterus Assess adnexae for masses/tenderness Perform cervical smear if necessary o Male 19

General: Height/Weight/BMI Fat and hair distribution Evidence of gynaecomastia or hypoandrogenism Groin: Check for inguinal hernias/masses Genitalia: Palpate testes and note site in scrotum Palpate epididymes for nodularity/tenderness Check presence of vas deferentia Check for presence of varicocoele Examine penis for structural abnormality

Investigation of Male Infertility o Semen Analysis Main Ix in males: if abnormal must repeat in 3mo Normal Values Volume 2-5mls Concentration > 20million/ml Motility > 50% progressive Morphology > 30% normal MAR Test (antisperm-Ab) Negative WCC < 1million/mL Abnormalities Azoospermia: No sperm Oligospermia: Reduced sperm concentration Asthenospermia: High proportion of poorly motile sperm Teratospermia: Morphologically defective sperm o Post-coital Test: Involves obtaining a sample of cervical mucus from the female partner 6 12 hours after intercourse to look for the presence of sperm o Endocrine Tests FSH: Should be measured in cases of azoospermia or severe oligospermia Testosterone: If hypogonadism is suspected Prolactin: Indicated in men complaining of impotence or loss of libido o Genetic Studies Karyotyping: If azoospermia or severe oligospermia are detected Cystic Fibrosis carrier screen: If absent vas deferentia detected

Investigation of Female Infertility o Hormonal Analysis Day 21 Progesterone: Level > 30nmol/l indicative that ovulation has occurred LH, FSH: Should be measured in the early follicular phase. LH:FSH ratio normally ~1:1. LH:FSH ratio of 2:1 or greater suggestive of PCOS TSH, Prolactin: Indicated if woman has amenorrhoea/oligomenorrhoea Testosterone, Sex-Hormone binding globulin: Should be performed if woman has significant hirsutism o Tests of Tubal Patency 20

Laparoscopy and dye hydrotubation Direct view of the pelvic organs enables inspection of fimbrial ends of tubes, pelvic organs Methylene blue dye is inserted through a cannula in the cervix to demonstrate tubal patency Invasive test/day case hospital admission/general anesthesia/risks of laparoscopy Recovery time 5-7 days Should be considered in patients with a history suggestive of endometriosis, previous PID or previous pelvic surgery Hysterosalpingography Injecting a radio-opaque contrast medium through the cervix into the uterine cavity and the fallopian tubes An x-ray is performed to see if there is spill into the peritoneal cavity Outpatient procedure, mild discomfort If normal the diagnosis can be relied upon in 97% of cases If abnormal a laparoscopy should be performed Ultrasound scan and hydrotubation Hysterosalpingocontrastsonography (HyCoSy) Ultrasonographic contrast medium is injected into the uterine cavity Ultrasound imaging is performed of the pelvic organs and of flow of the contrast medium along the tubes Allows assessment of uterine cavity Other Ix Transvaginal Ultrasound: largely superseded by laparoscopy and dye Hysteroscopy: Often performed with laparoscopy to assess uterine cavity Progesterone challenge test: useful in patient with amenorrhea and normal FSH. Medroxyprogesterone acetate 5mg daily for 5 days should induce a withdrawal bleed if this the patient is adequately estrogenized

Treatment o 20% of couples with subfertility conceive while awaiting investigations or treatment o Treatment depends on the underlying cause of the infertility o Anovulation Management Weight loss and lifestyle modification: Successful weight loss in patients with PCOS is associated with resumption of normal cyclical ovarian activity Improves response to ovulation induction agent Associated with lower rates of miscarriage and higher pregnancy rates Insulin-sensitizing agents PCOS associated with insulin resistance Metformin improves insulin sensitivity and reverses some of the metabolic features in PCOS Can be used alone or in combination with Clomiphene Ovlation Induction Agents Anti-Estrogens Clomiphene Citrate (Clomid) Mode of Action Binds to estrogen receptors in the hypothalamus reducing 21

negative feedback effect of endogenous estrogen GnRH and FSH secretion follicular recruitment & growth Taken for 5 days starting on day 2 of cycle (may need to give progesterone to induce a bleed) Start at lowest possible dose and increase if no response (check day 21 progesterone to determine response) Women should be monitored with US for the first cycle Side Effects Hot flushes 10% Pelvic/Abdominal discomfort 7% Nausea 2% Breast discomfort 2% Reversible hair loss Cholestatic jaundice Visual Disturbances Incidence of multiple pregnancy 7 10% 5% develop significant ovarian enlargement but OHSS is rare

Tamoxifen: similar action to Clomiphene Effectiveness of anti-estrogens Cumulative pregnancy rate of 60-70% over 6 mo w/ Clomiphene Tamoxifen equally effective Miscarriage rates 20-25%

Gonadotropins Human Menopausal gonadotrophin, Purified FSH, Recombinant FSH Used in patients who fail to conceive with clomiphene Also used in IVF cycles to stimulate ovulation Ultrasound monitoring vital risk of Ovarian Hyperstimulation Syndrome hCG is given when the dominant follicle is >17mm triggers ovulation

Ovarian Drilling Treatment option for anovulation associated with PCOS Performed laparoscopically 4 10 perforations created on surface of each ovary using laser or diathermy Similar success rates to ovulation induction with gonadotrophins No risk of multiple pregnancy, OHSS Risks: Risks of laparoscopy, damage to other pelvic structures, adhesion formation Anovulation and Hyperprolactinemia Prolactin inhibits pulsatile GnRH release form hypothalamus causing estrogen deficiency and anovulation Associated galactorrhoea in 30 80% Treatment: Bromocriptine, Cabergoline: Dopamine agonists Effective in normalising prolactin levels and restoring ovulation in 70 80% of patients

o Tubal Disesae Management Surgery 22

 IVF

Important to consider the patients age, site and extent of tubal damage, other factors influencing fertility Distal tubal occlusion has the worst prognosis Those w/ moderate-severe distal tubal occlusion have a better outcome with IVF Surgery is performed through a Pfannenstiel incision with microsurgical techniques used to restore tubal patency Women with previous tubal surgery have a 10 fold risk of ectopic pregnancy 1% of patients will request reversal after a sterilization success rates 31 90%

o Endometriosis Management No evidence that treating mild-moderate endometriosis w/ medication improves fertility Some evidence that surgery to ablate endometriotic lesions and divide adhesions improves fertility If pregnancy does not occur within 10 months it is reasonable to consider IVF o Male Factor Treatment Varicocoele: May be surgically ligated Surgery for varicocoele not indicated if semen analysis is normal Endocrine disorders: Hypogonadotrophic hypogonadism may be successfully treated with pulsatile GnRH administration Reversal of Vasectomy: Up to 80% success rates o Oligosopermia/Azoospermia Intrauterine insemination: Improves pregnancy rates in men with abnormal semen parameters ICSI/IVF: Direct injection of a single sperm through the outer membrane of the oocyte directly into the cytoplasm In obstructive azoospermia sperm may be extracted from epididymal fluid Assisted Conception o Intrauterine Insemination (IUI) Indications Unexplained Infertility Mild male factor infertility Coital or ejaculatory disorders Donor insemination Involves timed introduction of washed, motile sperm into the uterine cavity Sperm is prepared in a culture medium and only highly motile sperm are extracted This is placed with a fine plastic catheter into the uterine cavity May be used in conjunction with ovulation induction In unstimulated IUI urine or serum LH levels are monitored to detect LH surge this determines timing of insemination In stimulated IUI ultrasound monitoring is employed and when one follicle is > 16mm hCG is given to trigger ovulation and insemination is performed 24-48 hrs later o IVF

Indications 23

Male Factor Infertility Severe Endometriosis Failed Ovulation Induction Unexplained Infertility Egg Donation (not available in Ireland) Surrogacy (not available in Ireland) Pre-implantation diagnosis of genetic disease (not available in Ireland) Method of assisted reproduction where sperm and oocytes are mixed to allow fertilization in-vitro Resulting embryos are transferred into uterine cavity First performed successfully in 1978 Technique has been refined in recent years Combined with ICSI in severe male factor infertility

Technique Ovarian Stimulation: Pituitary is down regulated using GnRH analogues. FSH is then given to stimulate follicular recruitment and maturation. Response monitored with ultrasound. Oocyte Retrieval: Under ultrasound guidance a needle is passed through the lateral fornix of the vagina to aspirate follicles containing oocytes Insemination: 1) Freshly ejaculated seminal fluid is prepared and incubated with the retrieved oocytes. 2) ICSI - sperm injected directly into the oocyte Indication: sperm count <500,000 44% of IVF cycles now utilize ICSI Examined after 16 18 hours to ensure normal fertilization. Suitable embryos are incubated for a further 1-2 days Embryo transfer: Embryos transferred transcervically into uterine cavity through a soft plastic catheter. Usually max of 2 embryos transferred to risk of multiple pregnancy Luteal Phase Support: Pituitary downregulation can interfere with progesterone production during the luteal phase. Necessary to give hormonal supplementation either progesterone or hCG b/c it improves implantation and increases pregnancy rates Success Rates Affected by: Age of the woman: Significant decrease in success rates after age 35 Duration of infertility Previous unsuccessful treatment Previous pregnancies Sperm quality <35 years: 28.2% 35 37 years: 23.6% 38 39 years: 18.3% 24

40 42 years: 10.6% Ovum Donation Used in IVF when: Premature ovarian failure Bilateral oophorectomy Irreversible gonadal damage following chemotherapy or radiotherapy Certain cases of repeated IVF failure Success rates depend on age of donor

o Risks of Assisted Reproduciton Multiple Pregnancy Risk of multiple pregnancy with use of ovulation induction agents is 8 -10% with clomiphene and 15-20% with gonadotrophins Risk minimized by limiting no of embryos transferred Maximum of 2 embryos transferred per cycle In exceptional circumstances eg maternal age > 40, 3 embryos may be transferred Ovarian Hyperstimulation Syndrome Potentially life threatening effect of ovulation induction Occurs mainly with use of gonadotrophins Complicates 4% of ovulation induction cycles, severe in < 1% Underlying pathology is increased vascular permeability leading to fluid shift from intravascular to extravascular space

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Graded according to severity Mild: Bloating and mild abdominal pain Ovarian size < 8cm Moderate: Moderate pain, nausea, vomiting Ovarian size 8 12 cm Ascites Severe: Ascites +/- pleural effusion Haematocrit > 45% Ovarian size > 12 cm Risk of renal failure, VTE, acute respiratory distress syndrome and death Management Prevention: Ultrasound monitoring of ovulation induction Discontinue IVF cycle if estradiol levels are very high or an excessive no of follicles develop Treatment: Supportive analgesia, anti-emetics Monitor fluid balance 25

Thromboprophylaxis Abdominal paracentesis may be required

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