In girls and women aged between 15- to 34-years, infertility rates ranged from 7.3% to 9.1%. In women aged between 35- to 39-years, the infertility rates increase to 25%. Lastly, women aged between 40- to 44-years have a 30% chance of infertility. Worldwide, 2% of women aged between 20- to 44-years will never be able to have a live birth, and 11% with a previous live birth are unable to have an additional birth.1
What are the main causes of female infertility?
According to the World Health Organization (WHO) the most common causes of female infertility are:
- Ovulatory disorders - 25%
- Endometriosis - 15%
- Pelvic adhesions - 12%
- Tubal blockage - 11%
- Other tubal/uterine abnormalities - 11%
- Hyperprolactinaemia - 7%
Ovulatory disorders
Oligo-ovulation or anovulation results in infertility because no oocyte will be released monthly. In the absence of an oocyte, there is no opportunity for fertilisation and pregnancy. To help with treatment and further classification, the WHO subdivides ovulatory disorders into four classes:1
- Hypogonadotropic hypogonadal anovulation (e.g., functional hypothalamic amenorrhea [FHA]).
- Normogonadotropic normoestrogenic anovulation (e.g., polycystic ovarian syndrome [PCOS]).
- Hypergonadotropic hypoestrogenic anovulation (e.g., premature ovarian insufficiency [POI], previously known as premature ovarian failure).
- Hyperprolactinaemic anovulation (e.g., pituitary adenoma).
FHA in a nutshell
FHA is the cessation of the menstrual cycle in the absence of anatomical pathology, resulting from inadequate stimulation or suppression of the hypothalamic-pituitary-ovarian (HPO) axis.2
Both gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) pulsatility play pivotal roles in ovulation and maintaining a normal menstrual pattern. Various triggers, such as psychosocial stressors and energy imbalance, disrupt the pulsatile secretion of GnRH and LH in FHA.2
Bone health is a critical concern in FHA, as oestrogen stimulates bone formation and inhibits resorption. Given that peak bone mass is acquired <20-years, with substantial bone growth occurring during late adolescence, the impact on bone health in young patients with FHA is a major consideration. Hypoestrogenaemia and low lean mass in FHA patients contribute to potential bone health issues.2
Diagnosing FHA involves excluding other potential causes of secondary amenorrhea. Secondary amenorrhea is defined as the absence of menses for at least three consecutive months.2
FHA is characterised by low oestrogen levels, often below 50pg/ml, low follicle-stimulating hormone (FSH), often below 10mIU/mL, and low LH.2
Managing FHA requires accurate identification and reversal of underlying causes, often involving intensive lifestyle modifications to address maladaptive behaviours related to caloric intake and physical activity.2
A multidisciplinary approach, including medical healthcare professionals, dietitians, and mental health care professionals, is recommended whenever feasible.2
Current management recommendations rely largely on expert opinion and studies with limited sample sizes. There is a pressing need for research to assess various treatment modalities and develop new ones to address potential adverse long-term outcomes in FHA patients, including cognitive, psychological, bone, and cardiovascular (CV) health outcomes.2
PCOS in a nutshell
PCOS is the most common endocrinopathy affecting reproductive-aged women, with impacts across the lifespan from adolescence to post-menopause.3
PCOS prevalence is between 10% to 13%. PCOS aetiology is complex. Clinical presentation is heterogeneous with reproductive, metabolic, and psychological features.3
According to the 2023 International Evidence-based Guideline for the Assessment and Management of PCOS, diagnosis requires the presence of two of the following:3
- Clinical/biochemical hyperandrogenism.
- Ovulatory dysfunction.
- Polycystic ovaries observed through ultrasound.
An alternative approach is the use of anti-Müllerian hormone (AMH) instead of ultrasound. It is crucial to exclude other potential causes. Significantly, when irregular menstrual cycles and hyperandrogenism coexist, the diagnostic process is streamlined, rendering ultrasound or AMH unnecessary.3
In the case of adolescents, both hyperandrogenism and ovulatory dysfunction are prerequisites, with ultrasound and AMH not recommended due to their limited specificity.3
Furthermore, PCOS is characterised by insulin resistance. However, commonly used measures for insulin resistance are deemed inaccurate, and clinical assessment is presently not advised.3
Management of PCOS requires a holistic approach focusing on a healthy lifestyle, weight management, and minimising weight bias. No specific diet or exercise regimen is recommended.3
Combined oral contraceptives are the primary pharmacological choice for addressing menstrual irregularities and hyperandrogenism, with preference for formulations with lower ethinyl oestradiol doses and fewer side effects.3
Metformin is recommended for metabolic features, showing greater efficacy than inositol, but isn’t routinely advised during pregnancy. Laser therapy is effective for hair reduction, and anti-androgens are considered when other treatments are ineffective or contraindicated.3
For infertility, letrozole is the preferred first-line pharmacological therapy, followed by clomiphene with metformin, gonadotrophins, or ovarian surgery as second-line options.3
In vitro fertilisation (IVF) is a third-line consideration when other treatments fail, with a preference for single embryo transfer due to the heightened risk of pregnancy complications in PCOS.3
POI in a nutshell
POI mainly affect women younger than 40-years. Commonly, women present with amenorrhea for four to six months, low oestradiol levels, and elevated FSH level.4
POI is thought to arise from either follicular dysfunction or follicular depletion. However, the exact mechanisms in which POI develops remain unknown. About 90% of all diagnosed cases of spontaneous POI do not have a determined underlying aetiology.4
According to the 2023 British Menopause Society consensus statement, an apart from amenorrhea lasting >4 months, other signs include oligomenorrhea accompanied by elevated FSH (>40IU/l) on two occasions spaced four to six weeks apart in women <40-years. While AMH is not a routine diagnostic tool, it may be considered when the diagnosis is inconclusive.5
Women diagnosed with POI should receive guidance on lifestyle adjustments and bone health, emphasising a balanced diet, sufficient calcium and vitamin D intake, regular exercise, smoking cessation, and moderation in alcohol consumption.5
For managing menopausal symptoms in POI, systemic sex steroid hormone replacement is effective, and topical oestrogen preparations address urogenital atrophy symptoms.5 POI increases the risk of CV disease, osteoporosis, and cognitive impairment. Hormone replacement therapy (HRT) can mitigate these risks, aiming for physiological oestradiol levels until the natural menopausal age, unless contraindicated.5
While optimal regimens are unclear, both HRT and combined oral contraceptives are options, with HRT potentially offering superior bone health and CV benefits.5
Hormone replacement is the preferred strategy for osteoporosis prevention in POI. Bisphosphonates should be secondary and consulted with an osteoporosis specialist. Bone mineral density assessments at diagnosis and subsequent repeats, based on osteoporosis risk, are recommended.5
HRT doesn’t appear to heighten breast cancer risk in women <50-years. Limited evidence on venous thromboembolism risk in POI exists, but transdermal oestradiol may be a safer option, especially in those at risk.5
Women living with POI may have a 5%-10% chance of natural conception due to intermittent ovarian activity but assisted reproduction with their eggs is unlikely. Egg donation is more effective.5
Fertility preservation techniques are generally unsuccessful in established POI but can be considered for those at risk, such as those undergoing treatments affecting ovarian function or with a family history of POI.5
Pituitary adenoma in a nutshell
Pituitary adenomas, tumours in the anterior pituitary, are mostly benign and slow growing, classified by size (microadenoma <10mm, macroadenoma >10mm, giant >40mm).6
Women between the ages of 25- and 44-years are mostly affected. Pituitary adenoma prevalence varies widely in studies, estimated through autopsy and radiological data. A meta-analysis suggests an average frequency of 16.7%, with 14.4% in autopsies and 22.5% in radiological tests. Population-based studies report a prevalence of 115 per 100 000 population.6,7
Functioning adenomas cause hormone overproduction. The pathogenesis of pituitary adenoma is unclear. Most are sporadic, with rare genetic mutations. Genetic mutations in multiple endocrine neoplasia types 1 and 4, Carney complex, and familial isolated pituitary adenomas (FIPA) contribute, with aryl hydrocarbon receptor-interacting protein mutation in 15% of FIPA cases causing aggressive tumours, often secreting growth hormone and leading to acromegaly.6
Clinical signs of pituitary adenoma include hyperprolactinaemia (can lead to oligomenorrhoea or amenorrhoea) and hypogonadism (can lead to irregular menstrual cycles, infertility, and symptoms associated with oestrogen deficiency, such as hot flashes and vaginal dryness).7
Microadenoma, and, to a lesser extent, macroadenoma may induce deficiencies in the growth hormone, thyroid-stimulating hormone, and the adrenocorticotrophic hormone axes. It is essential to assess patients for related clinical manifestations, conduct tests for pituitary hormone deficiencies, and administer appropriate treatment.7
According to the Pituitary Society international consensus statement, published in 2023, dopamine agonist therapy proves highly effective in reducing serum prolactin levels, alleviating clinical manifestations of hyperprolactinaemia, and diminishing adenoma size. Discussions with patients should emphasise the prolonged need for dopamine agonist treatment and the limited likelihood of permanent cure.7
Cabergoline is the preferred choice due to its prolonged half-life, superior efficacy, and favourable tolerability. Bromocriptine and quinagolide are alternatives, contingent on accessibility.7
For microadenoma and well-encased macroadenoma, surgical risks and curative potential should be discussed in a multidisciplinary setting before initiating medical treatment.7
Neurosurgical resection of microadenoma and well-contained macroadenoma offers a high probability of cure, is cost-effective, and eliminates the need for long-term dopamine agonist treatment. Therefore, discussing surgery with a skilled pituitary neurosurgeon as a first-line option is strongly recommended for this patient subgroup.7
Medical treatment is the preferred initial approach for patients with a low likelihood of surgical remission. For cases of spontaneous cerebrospinal fluid rhinorrhoea, surgical repair is strongly recommended.7
Radiation therapy (RT) should be reserved for patients with inadequate adenoma shrinkage on dopamine agonists, and when residual adenoma persists post-surgery or when surgery is contraindicated. Stereotactic RT, if accessible, enhances outcomes.7
Patients should be aware that the response to RT may take several years. Lifetime follow-up is crucial to detect potential adverse effects, such as hypopituitarism, optic neuropathy, cranial nerve palsy, or second brain tumours, even occurring many years after treatment.7
Conclusion
Managing female infertility is challenging. Research indicates that ~85% of women conceive within a year, but fecundability diminishes over time. Ovulatory disorders, endometriosis, and tubal issues contribute significantly to female infertility. FHA requires a comprehensive approach, considering bone health and lifestyle modifications. PCOS management requires lifestyle modifications and pharmacotherapy, while POI management includes HRT. Pituitary adenomas management requires tailored dopamine agonist therapy or neurosurgical intervention. Awareness and effective management are vital for addressing these diverse reproductive challenges.
References are available on request.
