Sex, Infertility and Contraception

Core

Introduction

Sex, infertility and contraception sit together in the curriculum because each is the inverse of the next: the physiology of intercourse and conception explains why couples become pregnant; understanding why some couples do not conceive sets up infertility medicine; and contraception is the deliberate, reversible interruption of that same chain of events. This article addresses each topic at the level expected of a UK pre-clinical student. The underlying anatomy and the menstrual cycle are covered in Anatomy of the Man, Anatomy of the Woman and The Menstrual Cycle and Menstrual Abnormalities.

Sexual Response and Its Physiology

The Sexual Response Cycle

The classical Masters and Johnson model divides the human sexual response into four phases:

1. Excitement: central arousal, with peripheral effects driven by parasympathetic outflow: penile and clitoral engorgement, vaginal lubrication and labial swelling.
2. Plateau: sustained vasocongestion; in the male, the testes are drawn upwards and the bulbourethral glands secrete pre-ejaculate; in the female, the outer third of the vagina narrows ("orgasmic platform").
3. Orgasm: rhythmic contractions of pelvic floor and genital smooth muscle, mediated by sympathetic outflow. In the male this is coordinated with emission and ejaculation; in the female there are no obligatory accompanying secretions.
4. Resolution: vasocongestion subsides over minutes. The male enters a refractory period; women do not have an obligate refractory phase.

A useful memory aid is that parasympathetic outflow drives erection and sympathetic outflow drives emission and ejaculation. Both are coordinated by spinal centres in the lumbosacral cord with input from higher centres. The principles of autonomic control are set out in Autonomic Nervous System Introduction.

Erection, Emission and Ejaculation

An erection is a vascular event. Sexual stimulation triggers parasympathetic outflow from S2-S4 via the cavernous nerves, which release nitric oxide (NO) in the penile vascular smooth muscle. NO activates guanylate cyclase, raising intracellular cyclic GMP (cGMP); cGMP relaxes the smooth muscle of the helicine arteries supplying the corpora cavernosa. The corpora fill, compress the venous outflow against the rigid tunica albuginea, and the penis becomes erect.

cGMP is broken down by phosphodiesterase type 5 (PDE5), which is therefore the limiting step. PDE5 inhibitors: sildenafil, tadalafil, vardenafil: potentiate the same NO/cGMP pathway and are the first-line pharmacological treatment for erectile dysfunction. They are contraindicated with nitrates (cumulative cGMP accumulation can cause profound hypotension).

Once the male is sufficiently aroused, sympathetic outflow from T11-L2 produces:

• Emission: smooth-muscle contraction of the vas deferens, seminal vesicles and prostate, depositing semen into the prostatic urethra. The internal urethral sphincter contracts to prevent retrograde ejaculation into the bladder.
• Ejaculation: rhythmic contractions of the bulbospongiosus and ischiocavernosus muscles (somatic, pudendal nerve, S2-S4) propel semen out of the urethra.

Failure of the internal urethral sphincter to close (after prostatectomy, or with α-blockers such as tamsulosin used for benign prostatic enlargement) produces retrograde ejaculation: sperm passes back into the bladder, with cloudy post-coital urine and apparent infertility despite preserved orgasm.

Sexual Dysfunction

Sexual dysfunction is common and frequently has both physical and psychological components.

In men, the principal categories are:

• Erectile dysfunction: inability to achieve or maintain an erection. Causes include vascular disease (the most common in older men, sharing risk factors with artery disease), neurological disease (e.g. autonomic neuropathy in diabetes, spinal cord injury), endocrine causes (hypogonadism, hyperprolactinaemia, thyroid disease), drug-related (antihypertensives, particularly thiazides and β-blockers; antidepressants, particularly SSRIs; alcohol), and psychogenic (situational, performance-related). Clue to organic cause: loss of nocturnal/morning erections.
• Premature ejaculation: ejaculation occurring with minimal stimulation; treated with behavioural techniques and/or short-acting SSRIs (dapoxetine).
• Low libido / hypoactive sexual desire: consider depression, drug effect, hypogonadism.

In women, the principal categories are disorders of desire, arousal, orgasm, and sexual pain (dyspareunia, vaginismus). Pelvic pathology: endometriosis, vulvodynia, adhesions, postpartum changes: should be considered alongside hormonal and psychological factors. Postmenopausal women may have vaginal atrophy producing dyspareunia, treated effectively with topical oestrogens.

Infertility

Definitions and Epidemiology

Infertility is the failure of a couple to conceive after 12 months of regular unprotected intercourse. Investigation is brought forward to 6 months if the female partner is over 35, where there is known reproductive disease, or in the presence of obvious clinical pointers (e.g. amenorrhoea).

It affects approximately 1 in 7 couples in the UK. Of these:

• 30% of cases are predominantly female factor.
• 30% are predominantly male factor.
• 25% have combined factors.
• 15% are unexplained after a full work-up.

The single most powerful determinant is female age. Female fecundity falls steeply from the late 30s and very steeply after 40, reflecting both decreased oocyte number (ovarian reserve) and quality (rising aneuploidy rate).

Causes of Female Infertility

Female causes are conventionally split by anatomical site:

• Ovulatory disorders (around 25% of female infertility):
  • Polycystic ovary syndrome (PCOS): the commonest cause of anovulatory infertility in the UK; characterised by oligo- or anovulation, clinical or biochemical hyperandrogenism, and polycystic ovarian morphology on ultrasound (Rotterdam criteria, two of three).
  • Hypothalamic amenorrhoea: from low body weight, intense exercise, severe stress; reversed by restoring energy balance.
  • Hyperprolactinaemia: from prolactinoma, drugs (antipsychotics, metoclopramide), primary hypothyroidism. Suppresses GnRH and so suppresses ovulation. See Pituitary Disorders.
  • Premature ovarian insufficiency (POI): menopause before age 40; raised FSH, low oestradiol, low AMH.
  • Thyroid disease: both hyper- and hypothyroidism affect ovulation.
• Tubal disease (around 20%):
  • Previous pelvic inflammatory disease, particularly chlamydia.
  • Previous ectopic pregnancy or pelvic surgery.
  • Endometriosis with adhesion formation.
• Uterine and cervical factors:
  • Submucosal fibroids distorting the cavity.
  • Endometrial polyps.
  • Intrauterine adhesions (Asherman's syndrome).
  • Congenital uterine anomalies (e.g. septate uterus).
  • Cervical stenosis after surgery (e.g. LLETZ).
• Endometriosis: can cause infertility through tubal adhesion, distorted pelvic anatomy and unclear effects on egg quality and implantation.

Causes of Male Infertility

Male infertility is investigated through semen analysis. The principal mechanistic groups are:

• Pre-testicular (hormonal): hypogonadotrophic hypogonadism from pituitary disease, Kallmann syndrome, hyperprolactinaemia, anabolic steroid use (suppresses the hypothalamic-pituitary-gonadal axis).
• Testicular: primary gonadal failure: cryptorchidism (undescended testis), Klinefelter syndrome (47,XXY), Y-chromosome microdeletions, mumps orchitis, chemotherapy or radiotherapy, varicocele (raised scrotal temperature impairs spermatogenesis).
• Post-testicular (obstructive): absence of the vasa deferentia in cystic fibrosis (CBAVD), previous infection (epididymitis, gonorrhoea), previous vasectomy, ejaculatory duct obstruction, retrograde ejaculation.
• Lifestyle and environmental: smoking, alcohol, obesity, anabolic steroids, tight underwear / sauna use (mild and reversible).

Investigation

Investigation runs in parallel for both partners.

Female partner:

• Ovulation: day-21 (mid-luteal) progesterone: a value above 30 nmol/L confirms ovulation. If cycles are irregular, sample a week before the expected period.
• Ovarian reserve: day-2-5 FSH and oestradiol; anti-Müllerian hormone (AMH), the most useful single marker of ovarian reserve, can be sampled at any time in the cycle.
• Endocrine causes of anovulation: TSH, prolactin, total testosterone (in suspected PCOS).
• Pelvic anatomy: transvaginal ultrasound for ovarian morphology, fibroids, endometrial appearance, hydrosalpinges.
• Tubal patency: HyCoSy (hysterosalpingo-contrast-sonography) or HSG (hysterosalpingography) for low-risk women; laparoscopy with dye if pelvic pathology is suspected.
• Infection screen: chlamydia testing before tubal investigation.

Male partner:

• Semen analysis after 2-7 days of abstinence, assessing sperm concentration, total and progressive motility, and morphology against current WHO reference values. An abnormal sample is normally repeated approximately 3 months later (one full cycle of spermatogenesis) before being acted upon, except for azoospermia or severe oligozoospermia, where repeat testing is brought forward.
• Hormonal profile (FSH, LH, testosterone, prolactin) if azoospermia or severe oligozoospermia.
• Genetic testing (karyotype, Y-microdeletions, CFTR gene) if azoospermia or severe oligozoospermia.
• Scrotal ultrasound if a varicocele or anatomical abnormality is suspected.

Principles of Treatment

Treatment is matched to the cause:

• Lifestyle: normalise BMI (over- or underweight), stop smoking, reduce alcohol, recommend folic acid 400 micrograms daily for the female partner.
• Anovulation:
  • Letrozole: an aromatase inhibitor; now recommended as first-line for ovulation induction in PCOS by the 2023 International PCOS Guideline.
  • Clomifene citrate: an oestrogen receptor modulator that promotes a rise in FSH; previously the standard first-line; carries a risk of multiple pregnancy.
  • Gonadotrophin injections: reserved for cases that fail oral therapy, or for hypogonadotrophic hypogonadism.
  • Metformin: second-line in PCOS, with or without clomifene.
  • Treat underlying cause: dopamine agonists for hyperprolactinaemia, levothyroxine for hypothyroidism, weight restoration in hypothalamic amenorrhoea.
• Tubal disease: tubal surgery has limited results; in vitro fertilisation (IVF) is generally preferred. Hydrosalpinges are typically removed (salpingectomy) before IVF to improve outcomes.
• Endometriosis: surgical excision of severe disease can improve fertility; medical suppression (combined hormonal contraception, GnRH analogues) does not improve fertility and is reserved for symptom control.
• Male factor: mild abnormalities may be managed with intrauterine insemination (IUI); more severe abnormalities usually require IVF, often with intracytoplasmic sperm injection (ICSI). Where no sperm are present in the ejaculate, surgical sperm retrieval techniques may be considered.
• Unexplained infertility: expectant management for younger couples; IUI or IVF for older couples or those with extended duration.

NICE guidance currently recommends NHS funding for up to 3 cycles of IVF for women under 40 who meet eligibility criteria, though provision varies between integrated care boards.

Contraception

Effectiveness and Choice

Contraceptive efficacy is conventionally reported in two ways:

• Perfect-use failure rate: the failure rate when the method is used exactly as instructed.
• Typical-use failure rate: the failure rate seen in practice, including missed pills, late injections, condom slippage etc.

The two figures diverge most markedly for user-dependent methods, and barely at all for user-independent methods. This is the single strongest argument for long-acting reversible contraception (LARC):

• Implant (Nexplanon): typical-use failure < 0.05%/year: the most effective reversible method.
• Intrauterine device (Cu-IUD): typical-use 0.8%/year.
• Intrauterine system (IUS, e.g. Mirena): typical-use 0.2%/year.
• Depot medroxyprogesterone acetate (DMPA / "Depo-Provera"): typical-use ~6%/year.
• Combined hormonal contraception (pill, patch, ring): perfect ~0.3%/year, typical ~9%/year.
• Progestogen-only pill: perfect ~0.3%/year, typical ~9%/year.
• Male condom: perfect 2%/year, typical 18%/year.
• Fertility awareness: typical 24%/year.
• No method: approximately 85%/year.

Diagram: typical-use failure rates of contraceptive methods (FSRH and WHO data). The colour grouping highlights why long-acting reversible contraception (LARC) is markedly more effective in real-world use than user-dependent methods despite similar perfect-use figures.

Method choice should also consider non-contraceptive benefits (cycle control, acne, dysmenorrhoea), contraindications (thrombotic risk, migraine with aura, breast cancer history), reversibility, and the user's preferences and lifestyle. The UK Medical Eligibility Criteria (UKMEC) categorise risk by condition and method on a 1-4 scale:

• UKMEC 1: no restriction.
• UKMEC 2: advantages outweigh risks.
• UKMEC 3: risks outweigh advantages (use only if no alternative).
• UKMEC 4: unacceptable risk (do not use).

Combined Hormonal Contraception

Combined hormonal contraception (CHC) contains an oestrogen (most commonly ethinyloestradiol) and a progestogen, available as a pill, transdermal patch or vaginal ring.

Mechanism of action:

• Suppression of ovulation by negative feedback on the hypothalamic-pituitary axis: inhibits the mid-cycle LH surge.
• Thickening of cervical mucus.
• Thinning of the endometrium.

Non-contraceptive benefits include lighter, less painful, more predictable periods; reduced acne (particularly with anti-androgenic progestogens); reduced risk of endometrial and ovarian cancer (~50% with long-term use); and management of premenstrual symptoms and endometriosis.

Adverse effects and risks:

• Venous thromboembolism (VTE): baseline risk approximately 2 per 10,000 women-years, rising to 5-12 per 10,000 women-years on CHC depending on the progestogen (lowest with levonorgestrel, higher with desogestrel and drospirenone). Pregnancy itself carries a much higher VTE risk again.
• Small absolute increases in arterial events (myocardial infarction, ischaemic stroke), important in smokers, hypertensives and migraineurs.
• Breast cancer: small relative risk increase that returns to baseline within ~10 years of stopping.

The principal UKMEC 4 contraindications (combined hormonal contraception must not be used) are:

• Smoking 15 or more cigarettes per day in women aged 35 or older.
• Migraine with aura, at any age.
• Current breast cancer.
• Personal history of venous thromboembolism, or a known thrombogenic mutation.
• Current or past ischaemic heart disease, stroke or other arterial vascular disease.
• Severe or decompensated liver disease, or active hepatocellular tumour.
• Blood pressure ≥ 160/100 mmHg or vascular disease.
• Diabetes with vascular complications (nephropathy, retinopathy, neuropathy).
• Less than 6 weeks postpartum in women who are breastfeeding.
• Systemic lupus erythematosus with positive (or unknown) antiphospholipid antibodies.

Progestogen-Only Pill

The progestogen-only pill (POP) contains a progestogen only and is suitable for almost all women, including breastfeeding mothers, smokers over 35, and those with migraine with aura. Three formulations are available in the UK:

• Desogestrel-containing POPs (12-hour missed-pill window): work mainly by inhibiting ovulation, with additional cervical mucus thickening.
• Drospirenone-containing POPs (24-hour missed-pill window, with a hormone-free interval): the most recently introduced UK POP, also dominantly ovulation-inhibiting.
• Traditional POPs (e.g. norethisterone, levonorgestrel; 3-hour missed-pill window): work primarily by thickening cervical mucus; ovulation inhibition is less reliable.

The major drawback of POPs is unpredictable bleeding patterns: about a third of women have regular cycles, a third have irregular bleeding, and a third have amenorrhoea.

Long-Acting Reversible Contraception

UK guidance actively encourages LARC because of the gap between perfect and typical use of user-dependent methods.

Subdermal implant (Nexplanon). A 4 cm rod containing etonogestrel, placed in the upper arm and lasting 3 years. Mechanism: ovulation inhibition (dominant) plus cervical mucus effects. The most effective reversible method. Side effects: irregular bleeding (the commonest reason for removal).

Depot medroxyprogesterone acetate (DMPA, ‘Depo-Provera’). An intramuscular (or subcutaneous) injection every 13 weeks. Mechanism: ovulation inhibition. Distinctive features: associated with a reversible reduction in bone mineral density, which is generally most relevant in adolescents and around the menopause where alternatives may be preferred; UKMEC categorises both groups as 2 (advantages generally outweigh risks). Fertility may take up to 12 months to return after discontinuation.

Levonorgestrel-releasing intrauterine system (IUS, e.g. Mirena). A T-shaped device releasing levonorgestrel locally; lasts 5-8 years depending on the brand and indication. Mechanism: profound endometrial atrophy, thickening of cervical mucus, and a partial inhibition of ovulation. Reduces menstrual blood loss by > 90%; first-line for menorrhagia. Smaller doses (Kyleena, Jaydess) are useful for women who have not previously had children.

Copper intrauterine device (Cu-IUD). A T-shaped device with a copper wire; lasts up to 10 years. Mechanism: copper ions are toxic to sperm and ova, principally preventing fertilisation; effects on implantation are a secondary, weaker mechanism. Hormone-free, so suitable when hormonal methods are contraindicated. Tends to make periods heavier and more painful, the opposite of the IUS.

Both intrauterine devices carry the same insertion-related risks: uterine perforation (~1 per 1000 insertions), expulsion (~5% in the first year, mostly within the first 3 months) and pelvic infection (only just above background, and only in the first 3 weeks). If pregnancy occurs with an IUD/IUS in situ, the risk that the pregnancy is ectopic is increased (although the absolute risk of ectopic pregnancy is reduced compared to using no contraception).

Barrier Methods

Barrier methods physically prevent sperm reaching the cervix:

• Male condoms: the only method that simultaneously protects against most sexually transmitted infections, including HIV. Latex or polyurethane.
• Female condoms: less commonly used in the UK; same STI advantages.
• Diaphragms / cervical caps: rarely used in the UK; require fitting and concurrent spermicide.

Barrier methods are user-dependent and have a typical-use failure rate considerably higher than perfect-use figures.

Sterilisation

Sterilisation is a permanent contraceptive method.

• Vasectomy: division of the vasa deferentia under local anaesthetic; lower morbidity, higher effectiveness and lower cost than female sterilisation. Failure rate ~1 in 2,000. Requires confirmation of azoospermia on semen analysis 12 weeks after the procedure before contraception is stopped.
• Female sterilisation (laparoscopic tubal occlusion or salpingectomy): failure rate ~1 in 200; small risk of ectopic pregnancy if it does fail. Bilateral salpingectomy has largely replaced clip occlusion in the UK because it is more effective and reduces ovarian cancer risk.

Both should be regarded as irreversible at the point of consent.

Emergency Contraception

Three options are licensed in the UK:

1. Levonorgestrel (Levonelle): an oral progestogen, licensed up to 72 hours after unprotected intercourse. It works by delaying or inhibiting ovulation, and is ineffective once ovulation has occurred. Efficacy declines with time after intercourse. Available without prescription in the UK.
2. Ulipristal acetate (ellaOne): a selective progesterone receptor modulator, licensed up to 120 hours (5 days) after unprotected intercourse. It can delay ovulation even after the LH surge has begun, and is more effective than levonorgestrel, particularly close to ovulation. Simultaneous progestogen-containing contraception is avoided for 5 days afterwards because it can blunt the effect.
3. Copper intrauterine device (Cu-IUD): the most effective emergency contraception (failure rate < 0.1%); can be inserted up to 120 hours after unprotected intercourse, or up to 5 days after the earliest expected ovulation. Mechanism: copper ions are toxic to sperm and ovum and prevent implantation. The only method offering ongoing contraception once inserted.

The Faculty of Sexual and Reproductive Healthcare guidance is to offer the Cu-IUD first because of its superior efficacy, with oral options as alternatives where the IUD cannot or will not be used.

Fertility Awareness

Fertility-awareness methods identify the fertile window using cycle length, basal body temperature and cervical mucus signs (Billings method); modern apps and devices add hormonal sensors to refine this. Even with careful use the typical-use failure rate is ~24%/year, considerably higher than hormonal or intrauterine methods. They are nevertheless an important option for couples for whom other methods are unacceptable.

Summary

• The sexual response cycle is built from parasympathetic (engorgement) and sympathetic (orgasm) outflow. Erection depends on the NO-cGMP pathway, the target of PDE5 inhibitors.
• Infertility is investigated after 12 months of regular unprotected intercourse (6 months if > 35 or known disease). Causes split roughly evenly between male, female and combined factors with ~15% unexplained.
• Female investigation centres on day-21 progesterone, baseline gonadotrophins, AMH, thyroid and prolactin, pelvic ultrasound and tubal patency. Male investigation centres on semen analysis repeated at 6 weeks if abnormal.
• PCOS is the commonest cause of anovulatory infertility; ovulation induction is now first-line with letrozole.
• Contraceptive choice is shaped by effectiveness in typical use (LARC much better than user-dependent methods) and by individual contraindications captured in UKMEC.
• Three options are licensed for emergency contraception: levonorgestrel (72 h), ulipristal (120 h) and the copper IUD: the IUD is the most effective and the only one offering ongoing contraception.

Reviewed by: Dr. Marcus Judge

Quiz

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