Female hypogonadism (FH) is a common cause of period loss in women of reproductive age, but there are significant uncertainties and wide variation in its management.
Its treatment has hitherto been shaped by a combination of custom, clinical experience and study data relating to older, postmenopausal women. Existing clinical guidance on FH has largely focused on gynaecological practice, typically for specific conditions, such as premature ovarian insufficiency (POI).
'As with the Society guidance for male hypogonadism, our aim was to produce a document that would be enjoyable to read, while being informative and evidence-based.'
However, the diagnosis and management of different forms of FH have long remained a challenge for clinicians. The Society for Endocrinology commissioned new guidance to provide a multidisciplinary perspective on managing all forms of FH. Input was gathered from endocrinology, primary care, reproductive medicine/gynaecology and patients. As with the Society guidance for male hypogonadism, our aim was to produce a document that would be enjoyable to read, while being informative and evidence-based. We also chose to consider broader evidence encompassing transgender women, and to provide specific considerations for key forms of FH, such as Turner syndrome and functional hypothalamic amenorrhoea. The guidance is free-to-read in Clinical Endocrinology, and this article highlights some of its findings.1
DIAGNOSIS
The diagnosis of FH is not always straightforward. Women with POI frequently suffer for two years prior to diagnosis and treatment, despite multiple medical consultations. Diagnosis in women with central hypogonadism may take even longer, due to GPs’ poor awareness of its characteristic biochemistry. Although oligo-amenorrhoea is a prerequisite for the diagnosis of hypogonadism, there are other more common causes of menstrual disturbance, such as polycystic ovary syndrome and progestogenic contraceptives, and women with hypogonadism may instead be initially assumed to have one of these as the primary disturbance.
'The diagnosis of FH is not always straightforward. Women with POI frequently suffer for two years prior to diagnosis and treatment, despite multiple medical consultations.'
We no longer recommend progestogen challenge testing during the FH diagnostic pathway. We instead emphasise that a low serum oestradiol (E2) concentration (<200pmol/l) and/or thin endometrium (≤4mm) on ultrasound are consistent with FH when a woman has not experienced menstruation for several months. Alternative causes of a thin endometrium include systemic or intrauterine progestogen exposure, and following menstrual bleeding. Polycystic ovarian morphology on sonography should not distract clinicians from making a primary diagnosis of hypogonadism when the endometrium is thin, the uterus appears immature, or serum E2 is low (<200 pmol/l) in a woman without a recent period.
Previous reviews and guidelines have carefully avoided committing to any specific serum E2 threshold, perhaps due to concerns about assay variability, the focus of gynaecological practice on ultrasound findings, and the fear that it might distract from careful clinical phenotyping. However, consensus within our guideline group highlighted the pragmatic need to help steer generalists, as well as specialists, using serum E2 levels. Normative reference ranges for serum E2 are detailed yet unhelpful for diagnosing conditions such as FH. Therefore, we conducted a literature search for what might constitute an abnormally low E2 level in the context of prolonged amenorrhoea. An E2 threshold level <200pmol/l was agreed upon as an approximate threshold for women with lactational and hypothalamic amenorrhoea. Future studies may better define the biochemical threshold(s) for diagnosing FH.
MANAGEMENT
We strongly recommend that hormone replacement therapy (HRT) should be based on 17β-E2 rather than equine-derived oestrogens or ethinyloestradiol-based combined oral contraceptives (COCs). E2-based HRT allows monitoring of E2 levels if desired, minimises thrombotic risk (especially if transdermal), and optimises bone density and blood pressure compared with COCs. However, if contraception medication is required, then a modern E2-based (rather than ethinyloestradiol-based) COC is recommended.
We also note that many younger women require doses significantly higher than the maximum licensed doses for older, postmenopausal women. The specified minimum E2 doses for FH are 2mg orally or a 75μg transdermal patch, but higher doses may be required.
It is commonly advised that higher E2 doses should prompt an equivalent rise in progestogen for women with a uterus. This seems intuitively sensible, but we could find no evidence to support it. We recommend using a bioidentical neutral progestogen (micronised natural progesterone or its stereoisomer dydrogesterone), or a levonorgestrel-releasing intrauterine system which minimises systemic progestogen exposure.
The authors could not reach agreement on whether measuring serum E2 should also form part of routine monitoring. If serum E2 is checked, we recommend a target range as per most UK transgender women (300–600pmol/l) or the latest international Turner syndrome guidance (350–550pmol/l).
We recommend continuing HRT to at least the median age of menopause (51 years), but to consider continuing for longer when diagnosis and treatment were delayed, when there were prior frequent or prolonged gaps in therapy, or if bone density is concerning. Thereafter, the decision to continue HRT becomes a matter of informed patient choice as per menopausal HRT. Crucially, as HRT has fracture prevention data, we do not recommend adding any bone-specific drugs, except perhaps in exceptional circumstances. The guideline discusses special circumstances where concerns about HRT might be greater, and how these can be shared with patients and mitigated by adjustments to treatment, such as obesity, venous thromboembolism, ischaemic heart disease and meningioma.
'We hope this guideline helps non-specialists to distinguish FH from menopause, and supports specialists in current multidisciplinary practice for affected women.'
For women with functional central hypogonadism (hypothalamic amenorrhoea) due to relative energy deficit, opiates or hyperprolactinaemia, first-line treatments are lifestyle measures, analgesic dose-titration and prolactin-lowering measures respectively. However, we recommend starting HRT in the event that these measures are unsuccessful within 6–12 months or, indeed, without any delay if there is low probability that these approaches would be successful (e.g. in an athlete).
Fertility options are discussed in detail, but perhaps the most important take-home message is that gonadotrophin ovulation induction confers cumulative fertility rates approaching those of fertile couples when given to women with central hypogonadism.
FH is a diverse group of conditions affecting young women, the aetiology of which influences their management. We hope this guideline helps non-specialists to distinguish FH from menopause, and supports specialists in current multidisciplinary practice for affected women.
CHANNA N JAYASENA
Section of Investigative Medicine, Imperial College London
RICHARD QUINTON
CNTW NHS Foundation Trust, Newcastle upon Tyne, and Department of Metabolism, Digestion and Reproduction, Imperial College London
REFERENCE
1. Jayasena et al. 2024 Clinical Endocrinology https://doi.org/10.1111/cen.15097.
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