Endocrine Causes of Subfertility: Thyroid Disease, Hyperprolactinaemia, Congenital Adrenal Hyperplasia, and Obesity

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

• 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.

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).

• 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 (≥10 mm)

Dopamine Agonist Treatment

Dopamine agonists are first-line pharmacological treatment, restoring ovulatory cycles in >90% of cases:

• 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

• 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.

• 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

• 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

$$\text{BMI} = \frac{\text{weight (kg)}}{\text{height (m)}^2}$$

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

Management Summary

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