Overview
Endocrine dysfunction accounts for a substantial proportion of subfertility in women. The hypothalamic-pituitary-ovarian (HPO) axis is highly sensitive to perturbations in thyroid hormone, prolactin, adrenal androgens, and metabolic signalling. A systematic approach - serum TSH, prolactin, and androgen profiling - is essential in any woman presenting with anovulatory subfertility. This note covers thyroid disorders, hyperprolactinaemia, congenital adrenal hyperplasia (CAH), and obesity as discrete but interrelated endocrine causes of reduced fecundity.
Thyroid Disease and Fertility
Physiology and Mechanisms
Both primary hypothyroidism and primary hyperthyroidism disrupt ovulatory cyclicity and can cause amenorrhoea or oligomenorrhoea. Serum TSH is the gold-standard first-line screening test in any woman with ovulatory disturbance. In severe primary hypothyroidism, elevated TRH stimulates both TSH and prolactin secretion, compounding anovulation through secondary hyperprolactinaemia. Autoimmune thyroid disease (predominantly Hashimoto thyroiditis) is the most prevalent thyroid disorder in women of reproductive age and may impair fertility even without overt biochemical hypothyroidism.
Hypothyroidism and Reduced Fecundity
| Degree | TSH Range | Reproductive Impact |
|---|---|---|
| Overt hypothyroidism | $>10$ mIU/L | Anovulation, menstrual irregularity, elevated miscarriage risk |
| Subclinical hypothyroidism | $4$-$10$ mIU/L | Reduced fecundity, increased miscarriage risk; treat in women seeking pregnancy |
| Borderline | $2.5$-$4$ mIU/L | Contested association with miscarriage; not an independent treatment threshold |
| Treatment target (pre-conception / 1st trimester) | $<2.5$ mIU/L | Recommended target on levothyroxine |
| Treatment target (2nd-3rd trimester) | $<3.0$ mIU/L | Relax target after first trimester |
A TSH $>4$ mIU/L is the accepted threshold associated with measurably reduced fecundity and increased pregnancy loss. Levothyroxine is indicated in women seeking pregnancy at this level, targeting TSH $<2.5$ mIU/L before conception and during the first trimester. Women already established on levothyroxine who become pregnant should empirically increase their dose by approximately 25-30% as soon as pregnancy is confirmed, with TSH rechecked at 4-6 weeks and then each trimester. The mean full replacement dose is:
$$\text{Levothyroxine dose} \approx 1.6\ \mu\text{g/kg/day}$$
Postpartum, the dose should revert to the pre-pregnancy level, with a TSH check at 6 weeks postpartum.
Thyroid Antibody Positivity in Euthyroid Women
TPO-Ab positivity in biochemically euthyroid women is associated with higher rates of spontaneous miscarriage and lower live birth rates. The TABLET trial (UK RCT) examined whether levothyroxine 50 µg daily in euthyroid TPO-Ab-positive women reduced miscarriage rates and demonstrated no significant improvement in live birth rate or miscarriage rate. A separate 2017 RCT in euthyroid Chinese women with elevated TPO-Ab undergoing IVF similarly showed no benefit from levothyroxine 25-50 µg daily on miscarriage or live birth rates. Routine levothyroxine supplementation is therefore not recommended for euthyroid TPO-Ab-positive women outside a clinical trial context. These women should nonetheless be monitored during pregnancy given elevated risk of developing overt hypothyroidism.
Hyperthyroidism and Fertility
Hyperthyroidism (most commonly Graves disease) is associated with menstrual irregularity and oligomenorrhoea. Despite bidirectional effects on gonadotropins seen in thyrotoxicosis, most mildly-to-moderately affected women remain ovulatory; severe thyrotoxicosis causes anovulation and amenorrhoea more consistently.
| Management Consideration | Detail |
|---|---|
| Antithyroid drugs | PTU preferred in first trimester; carbimazole/methimazole in second/third trimester (PTU associated with hepatotoxicity with prolonged use) |
| Radioiodine ($^{131}$I) | Contraindicated in pregnancy; delay conception 6 months post-treatment |
| Post-radioiodine TRAb | TSH receptor antibodies (TRAb/TSHRAb) persist for years; risk of fetal-neonatal hyperthyroidism from transplacental passage even after maternal euthyroidism is restored; observed in 2-10% of pregnancies in women with current or prior Graves disease |
| Surgical thyroidectomy | Second trimester preferred if surgery is required in pregnancy |
Hyperprolactinaemia
Physiology: Prolactin Inhibition of GnRH Pulsatility
Prolactin secretion from anterior pituitary lactotrophs is tonically suppressed by hypothalamic dopamine via the tuberoinfundibular pathway. Excess circulating prolactin disrupts GnRH pulsatility - believed to occur via stimulation of hypothalamic dopaminergic neuronal activity that simultaneously inhibits GnRH pulse generator neurons. Consequences range from a shortened luteal phase (mild elevation) to anovulation to frank hypogonadotropic hypogonadism with oestrogen deficiency (severe elevation).
| Prolactin Level | Reproductive Consequence |
|---|---|
| $20$-$50$ ng/mL (mild) | Shortened luteal phase, subtle ovulatory dysfunction |
| $50$-$100$ ng/mL (moderate) | Oligomenorrhoea, anovulation |
| $>100$ ng/mL (severe) | Amenorrhoea, hypo-oestrogenism, bone loss; galactorrhoea in only ~one-third |
Galactorrhoea is present in only approximately one-third of women with hyperprolactinaemia because breast secretion also requires oestrogen, which is deficient in severe hyperprolactinaemia. Amenorrhoea without galactorrhoea is associated with hyperprolactinaemia in ~15% of women; in women with both galactorrhoea and amenorrhoea, approximately two-thirds have hyperprolactinaemia, of whom one-third have a pituitary adenoma.
Investigation
- Serum prolactin: single fasting, non-stimulated sample; repeat if borderline (avoid post-breast examination, venepuncture stress, post-prandial states)
- Exclude secondary causes: hypothyroidism (TSH), medications (antipsychotics, metoclopramide, opioids), renal failure, macroprolactin
- MRI pituitary fossa: indicated if prolactin persistently and significantly elevated; classifies microadenoma ($<10$ mm) vs macroadenoma ($\geq 10$ mm)
Dopamine Agonist Treatment
Dopamine agonists are first-line pharmacological treatment, restoring ovulatory cycles in $>90\%$ of cases:
| Agent | Dose | Efficacy | Notes |
|---|---|---|---|
| Cabergoline | 0.25-1.0 mg twice weekly | $>90\%$ ovulation restoration | Fewer side effects; preferred first-line |
| Bromocriptine | 1.25-2.5 mg 2-3× daily (start 1.25 mg nocte with food) | 80-90% normalise prolactin/restore ovulation | Nausea, vomiting, postural hypotension; vaginal administration (5 mg daily) if oral poorly tolerated |
Cabergoline is preferred for superior tolerability and compliance. Safety data from $>700$ pregnancies exposed at time of conception show no increased malformation or miscarriage risk above background rates.
Pregnancy with Prolactinoma
| Feature | Microprolactinoma ($<10$ mm) | Macroprolactinoma ($\geq 10$ mm) |
|---|---|---|
| Risk of symptomatic enlargement | ~1.6% | ~15% (highest risk in third trimester) |
| Dopamine agonist in pregnancy | Cease on confirmed pregnancy | Often continued throughout pregnancy |
| Pre-conception requirement | None beyond tumour confirmation | Neurosurgical/neuroendocrine review; document tumour shrinkage before conception; reducing risk of expansion to ~4% |
| Visual field monitoring | If symptomatic only | Formal visual field testing each trimester |
| Prolactin monitoring | Not useful (10× physiological rise) | Not useful in pregnancy |
| MRI | If symptomatic (no gadolinium) | If symptomatic |
Post-pregnancy remission: Following full-term pregnancy, a proportion of women with microprolactinoma experience long-term remission of hyperprolactinaemia. Assess postpartum prolactin level after cessation of breastfeeding before resuming dopamine agonist therapy.
Congenital Adrenal Hyperplasia and Fertility
Pathophysiology
CAH is an autosomal recessive disorder of adrenal steroidogenesis. 21-hydroxylase deficiency accounts for 90-95% of cases. Other enzyme defects (11β-hydroxylase, 3β-hydroxysteroid dehydrogenase) are rare. Deficient cortisol production drives compensatory ACTH hypersecretion, causing adrenal hyperplasia and excess androgenic precursor production.
| Mechanism | Reproductive Effect |
|---|---|
| Androgen excess (androstenedione, DHEAS, testosterone) | Suppression of HPO axis → anovulation, oligomenorrhoea, disrupted GnRH pulsatility |
| Elevated ACTH-driven androgens | Mimics PCOS phenotype; hirsutism, acne |
| Ovarian adrenal rest tumours (OARTs) | Ectopic adrenocortical tissue hyperresponsive to ACTH; adnexal masses, local ovarian parenchymal damage, impaired ovarian reserve |
| Relative progesterone deficiency | Luteal phase insufficiency |
Non-classical (late-onset) CAH may present subtly with hirsutism, oligomenorrhoea, and subfertility indistinguishable from PCOS. Diagnosis: basal 17-hydroxyprogesterone (17-OHP) $>6$ nmol/L, confirmed with ACTH stimulation testing (peak 17-OHP $>30$ nmol/L).
Fertility Management in CAH
- Glucocorticoid optimisation is the cornerstone: suppresses ACTH, reduces adrenal androgen excess, may restore ovulatory cycles
- Hydrocortisone or prednisolone preferred during pregnancy (not metabolised to active form by placental 11β-HSD2 - note dexamethasone crosses the placenta and is reserved for fetal adrenal suppression in at-risk pregnancies, not routine maternal management)
- OARTs: optimised glucocorticoid may reduce OART size; surgical resection risks permanent loss of ovarian tissue and should be avoided where possible
- Ensure optimal metabolic and hormonal control before ART
- Pre-implantation genetic testing (PGT) or prenatal diagnosis available for severe (salt-wasting) forms; partner carrier testing is appropriate given autosomal recessive inheritance
Obesity and Fertility
Pathophysiological Mechanisms
| Mechanism | Effect on Fertility |
|---|---|
| Aromatisation of androgens in adipose tissue | Elevated peripheral oestrone → relative oestrogen excess → negative feedback on FSH → impaired coordinated folliculogenesis despite ongoing anovulatory oestrogen production |
| Hyperinsulinaemia / insulin resistance | Increased LH pulsatility, excess ovarian androgen production, suppressed SHBG → elevated free androgens |
| Adipokine dysregulation (leptin excess, adiponectin deficiency) | Disrupts hypothalamic GnRH pulsatility and direct ovarian function |
| Chronic low-grade inflammation | Impairs oocyte quality and endometrial receptivity |
The paradox of obesity-related anovulation: ongoing anovulatory oestrogen from peripheral aromatisation persists despite failure of coordinated FSH-driven follicular development. This is distinct from hypothalamic amenorrhoea, where oestrogen is deficient.
BMI and Reproductive Outcomes
$$\text{BMI} = \frac{\text{weight (kg)}}{\text{height (m)}^2}$$
| BMI Category | Fertility Implications |
|---|---|
| $18.5$-$24.9$ (healthy weight) | Reference range |
| $25.0$-$29.9$ (overweight) | Modestly reduced fecundity, increased anovulation risk |
| $\geq 30$ (obese) | Significantly reduced fecundity, increased miscarriage risk, reduced ART success rates |
| $\geq 35$ (class II obesity) | Substantially impaired ART outcomes; elevated obstetric risk |
Weight Loss and Fertility Restoration
A weight loss of 5-10% of body weight can restore spontaneous ovulatory cycles in a significant proportion of obese anovulatory women and is first-line prior to ovulation induction or ART. Lifestyle modification (dietary change, physical activity) is the recommended initial approach.
Bariatric Surgery and ART
- Bariatric surgery (sleeve gastrectomy, Roux-en-Y gastric bypass) can restore ovulatory function and significantly improve metabolic parameters in morbidly obese women
- Conception should be delayed 12-18 months following bariatric surgery to allow nutritional stabilisation and weight plateau
- Nutritional deficiencies post-surgery (iron, folate, vitamin B12, calcium, vitamin D) must be assessed and corrected before conception
- ART outcomes (clinical pregnancy rates, live birth rates) are improved in post-bariatric surgery patients compared with matched obese controls, though data continue to accumulate
Investigations Summary
| Condition | Key Investigation | Diagnostic Threshold / Finding |
|---|---|---|
| Hypothyroidism | Serum TSH | $>4$ mIU/L = subclinical; $>10$ mIU/L = treat irrespective of symptoms |
| Thyroid antibodies | TPO-Ab, TgAb | Elevated = increased miscarriage risk even if euthyroid |
| Hyperthyroidism | Serum TSH, free T4, TRAb | Suppressed TSH; TRAb relevant for fetal/neonatal risk |
| Hyperprolactinaemia | Serum prolactin, MRI pituitary | Persistently elevated (>700 mIU/L) warrants MRI; exclude secondary causes |
| Non-classical CAH | Basal 17-OHP; ACTH stimulation test | Peak 17-OHP $>30$ nmol/L diagnostic |
| Obesity-related anovulation | BMI, OGTT, fasting insulin, SHBG, free androgen index | Identifies insulin resistance and metabolic syndrome components |
| Cushing syndrome (exclusion) | 24h urinary free cortisol; overnight dexamethasone suppression test | If clinical features present (hirsutism, rapid weight gain, striae, myopathy, hypertension) |
Management Summary
| Condition | First-Line Management | Key Monitoring |
|---|---|---|
| Subclinical hypothyroidism (TSH $>4$ mIU/L) seeking pregnancy | Levothyroxine; target TSH $<2.5$ mIU/L | TSH 4-6 weekly; increase dose ~25-30% on confirmed pregnancy; monthly TSH in pregnancy |
| Euthyroid TPO-Ab positive | Counselling and monitoring; levothyroxine not routinely recommended (TABLET trial) | TSH each trimester in pregnancy |
| Hyperprolactinaemia (anovulatory) | Cabergoline 0.25 mg twice weekly (first-line) | Prolactin levels; MRI if macroadenoma; visual fields |
| Microprolactinoma + pregnancy | Cease dopamine agonist on confirmed pregnancy | Symptom monitoring; MRI (no gadolinium) if symptomatic |
| Macroprolactinoma + conception planning | Neurosurgical/neuroendocrine review pre-conception; document tumour shrinkage first | Visual fields each trimester; usually continue dopamine agonist throughout pregnancy |
| Non-classical CAH | Glucocorticoid (hydrocortisone/prednisolone) to suppress ACTH/androgens | 17-OHP, androstenedione, cycle assessment |
| Obesity-related anovulation | Lifestyle modification; 5-10% weight loss before ART | BMI, OGTT, spontaneous cycle assessment |
| Post-radioiodine ($^{131}$I) | Delay conception 6 months; check TRAb if prior Graves disease | TRAb titre; fetal surveillance if TRAb positive in pregnancy |
Counselling Points
- Women with TSH $>4$ mIU/L seeking pregnancy should commence levothyroxine; normalisation of TSH will likely restore ovulatory cycles and reduce miscarriage risk
- Euthyroid women with thyroid antibodies carry elevated miscarriage risk, but current level I evidence (TABLET trial; 2017 IVF RCT) does not support levothyroxine to improve live birth rates; monitoring during pregnancy is appropriate
- Women with hyperprolactinaemia can be reassured that cabergoline restores fertility in $>90\%$ of cases; microprolactinoma carries a low (~1.6%) risk of symptomatic growth in pregnancy
- Women with macroprolactinoma require preconception specialist review and should be counselled about ~15% risk of symptomatic tumour expansion during pregnancy; this risk reduces to ~4% with pre-pregnancy tumour shrinkage
- In non-classical CAH, fertility can improve significantly with glucocorticoid optimisation; genetic counselling is appropriate given autosomal recessive inheritance (partner carrier testing relevant)
- Even modest (5-10%) weight loss meaningfully improves spontaneous conception rates and ART outcomes in obese anovulatory women and represents a safe, effective, cost-effective first-line approach
- Bariatric surgery candidates should delay pregnancy at least 12-18 months and address nutritional supplementation requirements; ovulatory function often normalises post-surgery
- Radioiodine is absolutely contraindicated in pregnancy; reliable contraception must be in place and pregnancy excluded before administration; conception should be delayed 6 months
Medicolegal and Ethical Considerations
- Failure to screen for thyroid dysfunction in women with anovulatory subfertility or recurrent pregnancy loss represents a potentially consequential missed diagnosis for both mother (untreated hypothyroidism) and offspring (neurodevelopmental impairment from inadequately treated maternal hypothyroidism in pregnancy)
- Prescribing levothyroxine to euthyroid TPO-Ab-positive women outside a clinical trial context is not supported by level I evidence; this should be clearly documented in counselling records
- Radioiodine is absolutely contraindicated in pregnancy; confirmed pregnancy must be excluded prior to administration, and reliable contraception discussed for 6 months post-treatment
- In women with macroprolactinoma, failure to arrange neurosurgical/neuroendocrine review prior to conception planning may result in preventable visual loss from tumour expansion during pregnancy
- Obesity management counselling must be conducted sensitively and without stigma; weight-related advice should be framed around evidence-based health optimisation, not aesthetic judgement
- Documentation of pre-treatment endocrine assessment prior to commencing ART is medically and medicolegally important; unexplained poor ART outcomes may prompt retrospective scrutiny of the pre-treatment workup