Medical maps: Fertility

So in this map we’re going to talk about (i) a couple of reproductive age who cannot conceive and (ii) climacteric symptoms and management. I will also cover (iii) contraceptive choices, but not as part of the medical map.

Inability to conceive

A couple is considered unable to conceive (‘subfertile’ or ‘infertile’) if conception does not occur despite regular unprotected sexual intercourse for one year.

An inability to conceive can be primary or secondary, and is distinguished from recurrent miscarriages:

  • Primary: couple has never conceived a child
  • Secondary: woman has previously been pregnant (regardless of outcome) and now cannot conceive
  • Recurrent miscarriages: three or more consecutive pregnancy losses – NOT considered infertility since conception has occurred; however, an inability to conceive and recurrent miscarriages have overlapping aetiologies

In general, 80% of females under 40 will conceive successfully within one year. 10% will conceive successfully in the next year. Therefore whilst the definition of an inability to conceive is one year without conception, treatment is only initiated after two years (in the UK).

When thinking about an inability to conceive, I divide the topic into female factor issues and male factor issues.

Female factor issues

The most helpful way to think about female factor issues is anatomically: causes within the reproductive tract and causes outside of the reproductive tract.

  • Within reproductive tract
    • Ovarian issues (40%)
      • Premature ovarian failure, defined as the cessation of ovarian function before the age of 40: triad of amenorrhoea, reduced oestrogen and elevated FSH
        • Primary (idiopathic)
        • Secondary (surgical removal, radiation, chemotherapy, inflammation, genetic syndromes)
      • Reduced ovarian reserve – fewer eggs available
      • Polycystic ovarian syndrome (see below)
    • Tubal issues (30%)
      • PID
      • Adhesions (e.g. from previous ectopic or its treatment)
      • Obstructions (e.g. tubal endometriosis)
    • Uterine issues (5%)
      • Fibroids
      • Asherman syndrome – intrauterine adhesions, associated with intrauterine instrumentation or infections
      • Anatomical defects – bifid uterus, unicornuate uterus
      • PID
    • Cervical issues (5%)
      • Antisperm antibodies (ASAs) in cervical mucus
      • Cervical anomalies
        • Stenosis
        • Inadequate mucus production
  • Outside reproductive tract
    • Sexual dysfunction (10%)
      • Vaginismus
      • Sexual arousal disorder
    • Endocrine dysfunction
      • Hypogonadotropic hypogonadism
      • PRLoma
      • Cushing’s syndrome
      • Thyroid disorders
      • Diabetes
    • Coeliac disease
    • Medication, alcohol, nicotine, drugs of abuse
IMG_0983

Female factor issues causing an inability to conceive. Click to enlarge.

More on: Polycystic Ovarian Syndrome (PCOS)

PCOS is a disorder of anovulation. Clinically, PCOS is diagnosed when two out of the following three Rotterdam criteria are fulfilled:

IMG_0986

The core features of PCOS, including the Rotterdam criteria for diagnosis. Metabolic syndrome is not part of the Rotterdam criteria but is a common feature of PCOS. Click to enlarge.

Although not part of the Rotterdam criteria, a fourth key feature of PCOS is metabolic syndrome related to the insulin-resistant state – including obesity and acanthosis nigricans.

Note that hyperandrogenism can be diagnosed clinically or from lab results (excess testosterone). Clinical hyperandrogenism manifests as virilisation: hirsutism (excess hair growth), breast atrophy, acne, increased muscle mass and deepening of the voice. If there are clinical features of hyperandrogenism, the criteria is fulfilled regardless of lab testosterone values.

However, before a diagnosis of PCOS is made, other conditions leading to hyperandrogenism and/or anovulation must be ruled out:

  • Pregnancy
  • Congentital Adrenal Hyperplasia
  • Cushing’s disease
  • Thyroid disease
  • Pituitary adenomas
  • Androgen or steroid intake

Treatment for PCOS involves treatment of the menstrual, metabolic and hormonal irregularities with or without treatment of infertility (if fertility is sought):

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PCOS treatment. Treatments for metabolic, hormonal and menstrual irregularities involve weight loss +/- metformin and combined hormonal contraception. Treatment for infertility – if fertility is desired – involves medical ovulation induction using clomifene, IVF or laparoscopic ovarian drilling. Click to enlarge.

Male factor issues

Male factor issues are thought to account for 30-50% of subfertility complaints. Again, divide the causes into within vs. outside the reproductive tract:

  • Within reproductive tract
    • Testicular
      • Cryptorchidism
      • Varicocele
      • Trauma
      • Orchitis – autoimmune or infections (e.g. mumps)
    • Vas deferens 
      • Obstructions
      • Congenital absence (e.g. cystic fibrosis)
      • Ligation
    • Semen disorders
      • Low semen volume
      • Low sperm motility
      • Low sperm counts
  • Outside reproductive tract
    • Sexual dysfunction 
      • Erectile dysfunciton
    • Endocrine dysfunction
      • Hypogonadotropic hypogonadism
      • PRLoma
      • Cushing’s syndrome
      • Thyroid disorders
      • Diabetes
    • Coeliac disease
    • Medication, alcohol, nicotine, drugs of abuse
IMG_0984

Male factor causes of an inability to conceive. Click to enlarge.

Investigating an inability to conceive

Investigating an inability to conceive involves taking a thorough history of both partners:

  • Any previous pregnancies/children? Any miscarriages?
  • How long have they been trying to conceive?
  • Any difficulties during sex?
  • Contraception status?
  • Medical history and surgical history?
  • Lifestyle – smoking, alcohol, drugs, weight, stress?

You can think about the investigations for female factor infertility as targeting specific parts of successful conception: the cervix, the process of ovulation and the patency of the fallopian tubes/uterus (typically done if other investigations are inconclusive). The first line investigations are a physical exam and mid-luteal serum progesterone:

  • Assessing the cervix: done with a physical examination consisting of an abdominal exam, speculum examination and bimanual pelvic exam
    • Swabs can be taken to test for ASAs
  • Assessing ovulation: endocrine tests + endometrial biopsy + temperature analysis
    • Endocrine tests
      • Mid-luteal serum progesterone defined as 7 days before the onset of the period (e.g. 28 day cycle – take at day 21)
      • FSH/LH levels which will be elevated in primary ovarian failure and reduced ovarian reserve
      • TSH levels which will be elevated in primary hypothyroidism – elevated TSH promotes prolactin (PRL) release which inhibits GnRH
      • PRL levels (PRLoma or hypothyroidism)
    • Endometrial biopsy
      • As far as I can tell this is rarely done in the UK in the context of an inability to conceive, but can be done to determine the endometrial thickness – if it is thin, it suggests a problem with the luteal phase
    • Temperature analysis
      • Often tracked with fertility apps; body temperature rises by about 0.5 degrees C from the follicular to luteal phase
    • *NOTE* The only sure-fire way of knowing that a woman has ovulated is a positive pregnancy test
  • Assessing the patency of the fallopian tubes +/- uterus generally done if first-line tests don’t reveal abnormalities, or there is a strong history suggestive of tubal obstructions
    • Hysterosalpingography (HSG) which involves radiocontrast injection into the uterus, combined with x-ray imaging
    • Lap-and-dye – more invasive requiring general anaesthesia, involving laparoscopic investigation of the pelvis together with dye injection into the uterus; can diagnose endometriosis, ovarian cysts together with potential obstructions
    • HyCoSy – a popular technique involving injection of agitated saline/air into the uterus under ultrasound imaging
      • It can be done at the same time as a conventional US scan
      • It doesn’t use radiation or iodinated contrast
      • It is less painful than HSG
IMG_0988

Assessing female causes of an inability to conceive. Key first steps involve (i) an assessment of the cervix using physical exam, and (ii) ovulation assessment using mid-luteal serum progesterone. If the results of these tests are inconclusive, the patency of the fallopian tubes can be assessed with HyCoSy, hysterosalpingography (HSG) or Lap & Dye. Click to enlarge.

Semen analysis is of critical importance when assessing male factor infertility:

IMG_0989

Components of semen analysis – the volume, quality and count is assessed. Click to enlarge.

  • Semen analysis involves checking volume, quality and sperm counts
    • Can also measure ASAs via an antiglobulin test
      • ASAs form if the blood-testis barrier (formed by the tight-junctions of Sertoli cells) is disrupted, due to trauma or infection
  • Hormone levels will often be done alongside semen analysis, including testosterone and FSH/LH
  • Imaging – US is almost always the initial imaging investigation, looking at testicular morphology, patency of efferent ducts and prostate anomalies

Climacteric and Menopause

Defining terms

People frequently refer to the ‘climacteric’ and menopause interchangeably, but they have distinct meanings:

  • Climacteric (aka perimenopause or menopausal transition): this is a time period around the menopause characterised by symptoms related to fluctuating hormonal levels, especially infrequent menstruation
    • 45-55 years of age
  • Menopause: 12 months of amenorrhoea – the official date is the last appearance of menstrual blood, determined retroactively
    • 49-52 years of age (51 is average)

Think of the climacteric as a period of time whereas the menopause is a single point in time, in an analogous way to puberty vs. menarche.

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Diagram explaining the climacteric (characterised by HAVOCS symptoms), menopause, premature menopause and surgical menopause. Click to enlarge.

Two additional terms:

  • Premature menopause is 12 months of amenorrhoea occurring before the age of 40
  • Surgical menopause is 12 months of amenorrhoea induced by removal of the ovaries (commonly hysterectomy with bilateral salpingo-oophorectomy)

(Patho)physiology, symptoms and diagnosis of the climacteric period

The pathophysiology of the climacteric period is straightforward: both the gamete releasing function and the sex hormone producing function of the ovaries gradually declines.

IMG_0991

The climacteric describes a period of declining ovarian function. A failure to release gametes results in fewer ovulatory cycles, fewer periods and ultimately the menopause. A reduction in sex hormone production (oestrogen and progesterone) leads to elevated gonadotropin levels sometimes used to diagnose the climacteric, and also HAVOCS symptoms. Click to enlarge.

In addition to irregular menstrual bleeding, the climacteric symptoms can be split into short, medium and long term:

  • Short term:
    • Hot flashes, mood changes, headaches, trouble sleeping
  • Medium term:
    • Urogenital atrophy, pelvic organ prolapse
  • Long term:
    • Increased osteoporosis risk
    • Increased cardiovascular disease risk

Climacteric symptoms can also be remembered with the mnemonic HAVOCS:

  • Hot flashes
  • Atrophy of the…
  • Vagina
  • Osteoporosis
  • Cardiovascular disease risk
  • Sleep disturbance

The diagnosis is mainly clinical, based on age and a pattern of increasingly infrequent menstrual bleeding ultimately leading to 12 months of amenorrhoea (menopause). Laboratory tests can help to confirm the diagnosis: reduced oestrogen leads to higher FSH/LH, with normal testosterone/PRL.

Managing climacteric symptoms

A subset of women will need management for climacteric symptoms – if they are severe, if there is premature menopause or if the menopause is surgical.

Treatment options include (i) lifestyle modifications, (ii) local medical therapies, (iii) systemic hormonal replacement therapy (HRT) or (iv) systemic non-hormonal medical therapies:

IMG_1002

Management options for climacteric symptoms. Click to enlarge.

HRT is usually employed for short-term treatment of psychoautonomic symptoms severe enough to interrupt daily function. HRT can be classified based on:

  • Hormone content – oestrogen only vs. oestrogen + progesterone.
  • Treatment regimen – cyclical (allowing for a withdrawal bleed, mimicking the menstrual cycle) or continuous
  • Method of delivery – oral or parenteral (patches, rings, gels, pessaries)

Before prescribing HRT, the benefits and risks of HRT must be discussed:

  • Benefits of HRT:
    • Management of psychoautonomic symptoms of the climacteric period
    • Protection against osteoporosis
    • Slight reduction in colon cancer risk
  • Risks of HRT: 
    • Oestrogen-only HRT:
      • Increases the risk of endometrial cancer (unopposed oestrogen)
      • Very slightly increases the risk of stroke
    • Combined HRT:
      • Increases the risk of breast cancer
    • Both types of HRT:
      • Very slightly increase the risk of ovarian cancer
      • Increased risk of DVT/PE with oral HRT (not patches or gels – they avoid first pass metabolism of the liver)
      • Increased risk of biliary disease – cholelithiasis, choledocholithiasis, cholecystitis

According to Cancer Research UK, “HRT is still an effective short-term treatment for [climacteric] symptoms, but has risks as well as benefits.”

If the decision is made to commence HRT, there are three important questions that need to be answered:

  • Should oestrogen only or oestrogen + progesterone therapy be used? This question is about the risk of endometrial cancer – unopposed oestrogen increases the risk of endometrial cancer
    • Does the lady have a uterus? If not, oestrogen only therapy can be used
    • If yes, is the a IUS in-situ? The IUS releases progesterone, so oestrogen only therapy can be used
  • Should therapy be cyclical or continuous? This question is about the date of the last menstrual period (LMP) and whether a lady needs to keep having periods 
    • Cyclical if a lady is still having periods (<1 year since LMP), to maintain regular periods so the lady is aware when her period naturally stops
    • Continuous HRT if the lady is post-menopausal (>1 year since LMP) where oestrogen/oestrogen+progesterone are taken every day
  • Should oestrogen be delivered orally or parenterally via a patch/ring/gel? This question is about (i) whether a lady would like to take tablets each day, and (ii) whether a lady has DVT/PE risk factors
    • Oral tablets are an option if the lady wants to take daily pills, and she doesn’t have significant DVT/PE risk factors
    • Parenteral/transdermal HRT – via rings, patches, gels, pessaries – if the lady doesn’t want to take pills or she has significant DVT/PE risk factors (including a BMI > 30)
    • [parenteral HRT avoids first pass metabolism of the liver, which is thought to be why it doesn’t increase the risk of DVT/PE]

I’ve tried to construct an algorithm based on these three questions. The figure below also outlines the benefits and risks of HRT:

IMG_1003

HRT algorithm shown left – based on the three questions you should be asking: (i) oestrogen monotherapy or combined oestrogen + progesterone; (ii) continuous or cyclical therapy (allowing for a withdrawal bleed); and (iii) the method of oestrogen delivery. Shown far right are the benefits/risks of HRT. Click to enlarge.

 

That’s it for HRT. Now the final part of our discussion on fertility: contraception.

Contraceptive choices

A contraception 101 – most of what you need to know for finals for contraception. It’s also a topic that can come up in obstetrics & gynaecology.

Types of contraception

Contraception can be non-hormonal or hormonal.

  • Non-hormonal
    • Behavioural methods
    • Barrier methods
    • Copper IUD
    • Surgical methods
  • Hormonal 
    • Combined hormonal contraception (CHC)
      • Oral pills (COCP – as 21 pills or 28 pills)
      • Rings
      • Patches
    • Progesterone only pill (minipill – 28 pills, take every day)
    • Parenteral progesterones
      • Implant – subdermal in upper arm, 1/3 become amenorrhoeic, 1/3 have fewer/lighter periods and 1/3 have troublesome irregular bleeding
      • Depot injections – given every 3 months and can induce amenorrhoea
      • IUS e.g. Mirena coil
    • (Emergency contraception)

‘The pill’ usually refers to the combined oral contraceptive pill (COCP). There are different ways to take the COCP:

  • 21 day pack – 21 active pills, then 7 days of no pills to allow for a withdrawal bleed
  • 28 day pack – 21 active pills, then 7 days of placebo to allow for a withdrawal bleed (useful if someone wants to take a pill every day so it becomes a ‘habit’)
  • Tricycling – taking 3 x 21 active pills and then allowing 7 days for a withdrawal bleed
  • Continuous dosing – keep taking active pills until there is spotting, then stop for 7 days to allow for a withdrawal bleed

The progesterone-only ‘minipill’ is taken everyday, coming in packs of 28.

How do the different types of contraception work?

Barrier methods (condoms, diaphragms, caps) block sperm fertilising the egg. The copper IUD is spermicidal.

Hormonal methods containing oestrogen inhibit ovulation. Progesterone-containing methods thicken cervical mucus, thin the endometrial lining and may inhibit ovulation although this is not consistent.

Deciding on the type of contraception

Once the lady is well-informed of the different types of contraception, there are two important considerations. First, what type of contraception does the woman want? Second, is the method safe to use? 

Factors which could influence the answer to the first question:

  • How effective is the method?
    • There are different values for the number of pregnancies with perfect use (called the ‘Pearl index’) or actual use.
  • Do I want something that is less effort to remember? 
    • Methods like the IUS/IUD, implant and injection don’t require a pill to be taken every day.
  • Do I want something without hormones? 
    • The copper coil, barrier methods, behavioural methods and surgical methods all lack hormones.
    • NB/ hormones in contraceptives are very similar to bodily hormones, the key difference is they produce an even level of hormone rather than cyclical variation.
  • When do I next want to be pregnant? 
    • If pregnancy is desired in the next few months, something easy to stop – like a pill or barrier method – is suitable.
  • Do I want regular periods? 
    • Non-hormonal methods allow for periods. The combined pill can have a regular withdrawal bleed which mimics a period. It can also be taken continuously to avoid a period.
  • Do I want lighter/less painful periods? 
    • Hormonal methods, both combined and progesterone-only, are good at making periods lighter.

To address the second question, the UK Medical Eligibility Criteria (UKMEC) are available which list contraindications for particular contraceptives.

  • Category 1: no restriction to use of the method
  • Category 2: benefits generally outweigh risks
  • Category 3: risks generally outweigh benefits
  • Category 4: unacceptable health risk with method

Category 4 examples include combined hormonal contraceptive use in a patient with migraine+aurabreast cancer or VTE history.

Emergency contraception

There are three types of emergency contraception for unprotected sexual intercourse (UPSI):

  • Levonorgestrel pill, which releases progesterone (‘Plan B’)
    • Use ASAP for it to be most effective, but it is effective when placed within 72 hours
  • Uilpristal acetate, a selective progesterone receptor modulator (SPRM, called ellaOne)
    • Use ASAP for it to be most effective, but it is effective when given within 120 hours
  • Copper coil IUD, spermicidal
    • This is the most effective at preventing pregnancy
    • It can be inserted within 120 hours, or within 5 days of predicted ovulation date

Below is a diagram outlining the contraceptive methods based on timing:

IMG_1004.jpg

Emergency contraception options following unprotected sexual intercourse (UPSI). The levonorgestrel ‘Plan B’ pill can be used 72 hours after UPSI but is more effective the sooner it’s used. The ulipristal acetate progesterone modulator can be used 120 hours after UPSI; again it is more effective the sooner it is used. The copper IUD is the most effective method – it can be used 120 hours after an UPSI or up to 120 hours after the predicted ovulation date. One potential benefit of the IUD is it provides lasting protection against future unplanned pregnancies. Click to enlarge.

 

Missed pill rules

late pill is a pill taken after the due time but before 24 hours have elapsed. A missed pill is failing to take the pill after 24 hours have elapsed.

The missed pill rules are different for the COCP and the minipill because they work in different ways:

  • The COCP mainly works by inhibiting ovulation
  • The minipill mainly works by thickening cervical mucus

For the COCP, action is needed if two pills are missed as shown below; the nature of the action depends on the week in which the pill was missed:

IMG_0995

Late and missed pill rules for COCP. Click to enlarge.

Why are there these complex rules for two missed pills? I think about it in terms of ovarian activity and the ovaries needing to reach an ovulation threshold to release an egg.

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The science behind the COCP two missed pill rule. Missing two pills in the first week or the third week is associated with a risk of breakthrough ovulations and therefore unplanned pregnancy if not managed. Click to enlarge.

The minipill works by thickening cervical mucus – the effects wear off quickly. This means even a late pill (the definition of ‘late’ depends on the type of progesterone – it can either be 3 hours or 12 hours) can affect protection vs. pregnancy.

IMG_0998

Minipill late/missed pill rules. Simpler than the COCP. Click to enlarge.

The minipill’s effects on cervical mucus take 2 days to establish so extra precautions should be taken for 2 days following a late/missed pill.

A quick aside – an easy way to remember the different names for progesterones is ‘LDN’ (like London):

  • Levonorgestrel (3 hour)
  • Desogestrel (12 hour)
  • Norethisterone (3 hour)

Summary

When helping someone decide between contraceptive methods, you must (i) inform them of the benefits and risks; (ii) allow them to express their preference; and (iii) be aware of the UKMEC criteria and absolute contraindications against using particular methods.

Medical map: fertility

Here is the map for fertility issues: an inability to conceive and the climacteric/menopause. I haven’t included the contraception details.

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Medical map for fertility issues – inability to conceive and climacteric/menopause. Click to enlarge.

Hope it helps!

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