Hypogonadism

Loss of gonadal function of any cause. Diagnosis requires testing of sex hormone and gonadotropin levels. This section includes absent or delayed puberty, primary testicular failure, premature ovarian failure, and secondary hypogonadotropic hypogonadism.

Male late onset hypogonadotropic hypogonadism


Repeat 9am testosterone, SHBG and albumin

Management decisions should not be taken on an isolated testosterone level. Borderline levels (typically between 8-12nmol/l) should be interpreted in the light of SHBG and albumin to calculate a free androgen index.


Review baseline pituitary function

If there is any doubt, consider dynamic function testing to confirm isolated nature of hypogonadism.


MRI pituitary

With isolated hypogonadotropic hypogonadism, the pituitary is likely to be structurally normal. If the hypogonadism is mild (eg testosterone >6nmo/l), isolated and of late onset eg associated with adiposity and type 2 diabetes mellitus, imaging may not be requried. For more severe cases, a structurally normal pitutiary on MRI scanning is reassuring that no further imaging need be undertaken in the future.


Consider DEXA scan

Documented low bone mineral density will inform decision whether to initiate treatment.


Discuss fertility issues

This should be discussed at, or soon after, diagnosis. Semen analysis, counselling, and referral to a fertility clinic for consideration of spermatogenesis induction, should be offered if appropriate.


Testosterone confirmed low with no other abnormalities detected: start treatment

Discuss whether treatment is actually required in each individual case. The presence of sexual symtpoms - loss of libido and early morning erections are the most specific to androgen deficiency and are likely to improve with treatment. Other symptoms such as fatigue, poor muscle strength and erectile dysfunction are often multifactorial and may respond better to non hormonal treatments.

If a trial of treatment is indicated, discuss the different testosterone preparations available, for example daily topical gel, patch, or regular or depot injections.

It is appropriate to start treatment at the usual adult dose in patients with adult onset hypogonadism, and continue for 3 months before determining clinical response.


Optimise dose according to symptoms and serum levels

Routine monitoring of serum testosterone levels is not necessary until the expected adult dose is reached.

Peak and trough levels may then be useful to confirm the appropriateness of the final dose in patients taking monthly testosterone undecanoate. Peak 7 days post injection should typically be 25-30nmol/l, with a predose trough level of 8-12nmol/l. Subsequently, the dose should not be altered unless the clinical response is suboptimal, or in the light of changes in serum monitoring of prostate specific antigen, full blood count, liver function, or pre dose testosterone levels.

In patients taking depot preparations, a random or pre dose level of 15-20nmol/l, and for patients taking daily topical preparations, a level of 15-20nmol/l 4-6 hours post application of the gel is usually suficient.


Annual monitoring and follow up

After the dose has been optimised, annual random levels are sufficient in most cases, with pre dose levels also required in patients on testosterone ester injections. Digital rectal examination, prostate specific antigen, full blood count and liver function tests should also be performed annually with dose reduction and or onward referral if abnormalities arise.

Specialist follow up is not usually required long term.

Female late onset hypogonadotropic hypogonadism


Review baseline pituitary function

If there is any doubt that hypogonadotropic hypogonadism may not be isolated, consider dynamic function testing.


MRI pituitary

Late onset isolated hypogonadotropic hypogonadism is uncommon in females requiring thorough investigation for other causes.


Consider DEXA scan

Documented low bone mineral density will inform decision as whether to initiate treatment, and whether other agents should be considered, for example bisphosphonates and vitamin D.


Discuss fertility issues

This should be discussed at, or soon after, diagnosis and counselling or referral offered if appropriate.


Initiate treatment

Cyclical estrogen and progesterone replacement therapy should be considered in all patients.

The combined oral contraceptive pill is a convenient preparation and may be more socially acceptable at diagnosis and in young patients. However, there has been some doubt as to whether this offers sufficient bony protection unless taken continuously, with some authorities advising taking this 3 packs at a time. Combined oral contraceptive pills are also contraindicated in patients with a history of migraines with aura. Low dose HRT is more suitable in these cases.

Hormone replacement therapy is more appropriate in the long term, and should be tailored to suit the individual, for example by offering topical, depot or oral preparations. Choice will also depend on the age of the patient, presence or absence of a uterus, and history or family history of breast or endometrial cancer. A history of, or strong risk factors for cardiovascular or thromboembolic disease will also need to be considered. 

Topical estrogen is particularly useful in patients at high cardiovascular risk, or with abnormalities of liver function. Combined patches are available, or if estrogen gel is used, low dose continuous progesterone will also be required to prevent endometrial hyperplasia eg 1x350mcg progesterone only pill daily.

Estrogen replacement therapy should be continued until the time of the natural menopause - typically to age 50. Vaginal dryness may be ameliorated by topical estrogen gels.

Male hypergonadotropic hypogonadism


Repeat 9am testosterone, SHBG and albumin

Management decisions should not be taken on an isolated testosterone level. Borderline levels should be interpreted in the light of SHBG and albumin to calculate a free androgen index.


Testicular ultrasound

If there is any doubt about the aetiology of gonadal failure, imaging should be performed and further investigation undertaken, for example with tumour markers (alpha feto protein and human chorionic gonadotropin) and urology referral. 


Thyroid auto-antibody screen

Primary gonadal failure may be associated with other organ specific auto-immune diseases and so such patients should be screened and monitored for their development.


Vitamin B12, coeliac auto-antibody screen

Primary gonadal failure may be associated with other organ specific auto-immune diseases and so such patients should be screened and monitored for their development.


Consider DEXA scan

Documented low bone mineral density will inform decision whether to initiate treatment, and whether other agents such as calcium and vitamin D are required.


Discuss fertility issues

This should be discussed at or soon after diagnosis. Semen analysis, counselling and referral to a fertility clinic should be offered if appropriate.


Testosterone confirmed low with no other abnormalities detected: start treatment

Discuss whether treatment is actually required and the different testosterone preparations available, for example topical gel, patch, regular or depot injections.

Treatment is usually started at standard adult doses in patients with adult onset hypogonadism.


Optimise dose according to symptoms and serum levels

Routine monitoring of serum testosterone levels is not necessary until the expected adult dose is reached.

Peak and trough levels may then be useful to confirm the appropriateness of the final dose in patients taking monthly testosterone undecanoate. Peak 7 days post injection should typically be 25-30nmol/l, with a predose trough level of 8-12nmol/l. Subsequently, the dose should not be altered unless the clinical response is suboptimal, or in the light of changes in serum monitoring of prostate specific antigen, full blood count, liver function, or pre dose testosterone levels.

In patients taking depot preparations, a random or pre dose level of 15-20nmol/l, and for patients taking daily topical preparations, a level of 15-20nmol/l 4-6 hours post application of the gel is usually sufficient.


Annual monitoring and follow up

After initial dose optimisation, annual random levels are sufficient in most cases, with pre dose levels for those taking regular injectable preparations.

Digital rectal examination, prostate specific antigen, full blood count and liver function tests should also be performed annually with dose reduction and or onward referral if abnormalities arise.

B12, 9am cortisol, TSH and free thyroxine should be assessed annually where the cause is presumed to be auto-immune.

Specialist follow up is not usually required long term.

Female hypergonadotropic hypogonadism


Thyroid auto-antibody screen

Primary ovarian failure is associated with other organ specific auto-immune diseases and so such patients should be screened and monitored for their development.


Vitamins B12, coeliac auto-antibody screen

Primary ovarian failure is associated with other organ specific autoimmune diseases and so such patients should be screened and monitored for their development.


Consider DEXA scan

Documented low bone mineral density will inform decision whether to initiate treatment, and whether other agents should be considered, for example bisphosphonates and vitamin D.


Discuss fertility issues

This should be discussed at, or soon after, diagnosis and counselling or referral offered if appropriate.


Initiate treatment

Cyclical estrogen and progesterone replacement therapy should be considered in all patients.

The combined oral contraceptive pill is a convenient preparation and may be more socially acceptable at diagnosis and in young patients. However, there has been some doubt as to whether this offers sufficient bony protection unless taken continuously, with some authorities advising taking this 3 packs at a time. Combined oral contraceptive pills are also contraindicated in patients with a history of migraines with aura. Low dose HRT is more suitable in these cases.

Hormone replacement therapy is more appropriate in the long term, and should be tailored to suit the individual, for example by offering topical, depot or oral preparations. Choice will also depend on the age of the patient, presence or absence of a uterus, and history or family history of breast or endometrial cancer. A history of, or strong risk factors for cardiovascular or thromboembolic disease will also need to be considered. 

Topical estrogen is particularly useful in patients at high cardiovascular risk, or with abnormalities of liver function. Combined patches are available, or if estrogen gel is used, low dose continuous progesterone will also be required to prevent endometrial hyperplasia eg 1x350mcg progesterone only pill daily.

Estrogen replacement therapy should be continued until the time of the natural menopause - typically to age 50. Vaginal dryness may be ameliorated by topical estrogen gels.


Monitoring and follow up

Estrogen replacement therapy requires no routine monitoring unless the patient is symptomatic, for example menstrual irregularity or hot flushes.

Annual monitoring of TSH, free thyroxine, 9am cortisol and vitamin B12 level should be initiated to screen for the development of other associated conditions.

Specialist follow up may not be required long term.

Absent puberty (any cause)


Discuss treatment aims, timescales and outcomes

Treatment aims to replicate the natural process of puberty and should occur over approximately the same timescale - approximately two to three years.

Adult patients should be warned that accelerating the process may have adverse long term psychological and physical consequences, for example poor breast development.


Discuss fertility issues at, or soon after, diagnosis

If appropriate, fertility should be discussed early with the patient and their family.

Patients need to understand that successful pubertal induction will not affect or restore fertility, although appropriate uterine development is necessary prior to possible future pregnancies.


Karyotype analysis

Adult patients with absent puberty require karyotype analysis to differentiate between different causes, for example Klinefelter's syndrome, androgen insensitivity or Turner's syndrome.


Review baseline pituitary function

If there is any doubt that hypogonadotropic hypogonadism may not be isolated, consider dynamic function testing.


MRI pituitary

If karyotype is normal, and cause of hypogonadotropic hypogonadism is uncertain, thorough investigation for other causes should be performed.


Consider assessing bone age

Delayed bone age supports the diagnosis of absent puberty.


Initiate treatment: females

Initiate very low dose estrogen replacement therapy.

An alternative is to use topical estrogen therapy. This may give a better eventual breast shape, and is well tolerated, with the patches often easier to source in the community than low dose ethinylestradiol. A typical start dose is with one quarter of a 25mcg Estradiol patch given either overnight every day, or left on and replaced every 72 hours. The dose should then increase every 3-4 months to half a patch, then a whole 25mcg patch, then a 50mcg patch, then a 75mcg, then a 100mcg patch.  


Dose titration

Consider pelvic ultrasound scan to assess uterine size at this stage.

Once the patient experiences vaginal bleeding or if the patient has tolerated 15mcg orally, or 100mcg transdermally, consider adding cyclical progesterone. Measurement of LH and FSH levels may also be used to help judge whether the final dose of topic estradiol is sufficient, as some girls will require higher doses.


Alternative treatment regimens

Cyclical estrogen and progesterone replacement therapy should be considered in all patients.

The combined oral contraceptive pill is a convenient preparation and may be more socially acceptable at diagnosis and in young patients. However, there has been some doubt as to whether this offers sufficient bony protection unless taken continuously, with some authorities advising taking this 3 packs at a time. Combined oral contraceptive pills are also contraindicated in patients with a history of migraines with aura. Low dose HRT is more suitable in these cases.

Hormone replacement therapy is more appropriate in the long term, and should be tailored to suit the individual, for example by offering topical, depot or oral preparations. Choice will also depend on the age of the patient, presence or absence of a uterus, and history or family history of breast or endometrial cancer. A history of, or strong risk factors for cardiovascular or thromboembolic disease will also need to be considered.

Topical estrogen is particularly useful in patients at high cardiovascular risk, or with abnormalities of liver function. Combined patches are available, or if estrogen gel is used, low dose continuous progesterone will also be required to prevent endometrial hyperplasia eg 1x350mcg progesterone only pill daily.

Estrogen replacement therapy should be continued until the time of the natural menopause - typically to age 50. Vaginal dryness may be ameliorated by topical estrogen gels.


Duration of treatment

Continue sex hormone replacement therapy until the time of the natural menopause - typically to age 50.


Follow up

Offer life long follow up to all patients.

Consider periodic monitoring of bone densitometry and of pituitary function where indicated.

Patients with Turner’s syndrome, Klinefelter’s, Kallmann’s or underlying pituitary disease will require specific follow up.


Initiate treatment: male patients

Initiate very low dose testosterone therapy, and warn patient of expected psychological and physical effects.

Typical starting dose in a testosterone naive patient is approximately 20% of the usual adult dose. This has traditionally been given as 50mg testosterone ester as an intramuscular injection, monthly, though an alternative is to use very low dose daily testosterone gel using a metered dose delivery system.


Dose titration

Monthly testosterone treatment is then typically increased by a further 50mg every six months according to clinical response.

Alternatives include low dose depot testosterone, or topical gel using the same dosing schedule.


Treatment monitoring

Routine monitoring of serum testosterone levels is not necessary until the expected adult dose is reached.

Peak and trough levels may then be useful to confirm the appropriateness of the final dose in patients taking monthly testosterone undecanoate. Peak 7 days post injection should typically be 25-30nmol/l, with a predose trough level of 8-12nmol/l. Subsequently, the dose should not be altered unless the clinical response is suboptimal, or in the light of changes in serum monitoring of prostate specific antigen, full blood count, liver function, or pre dose testosterone levels.

In patients taking depot preparations, a random or pre dose level of 15-20nmol/l, and for patients taking daily topical preparations, a level of 15-20nmol/l 4-6 hours post application of the gel is usually sufficient.


Alternative treatments

Once patient is virilised appropriately and established on full adult dose, offer switching to alternative preparation, for example daily gel or depot preparation.

Optimise final dose according to symptoms and serum levels.


Annual monitoring

Annual random levels are sufficient in patients on topical and depot preparations. Annual pre dose levels are required in those on injectable testosterone esters. 

Digital rectal examination, prostate specific antigen, full blood count and liver function tests should also be performed annually with dose reduction and onward referral if abnormalities arise.


Follow up

Offer life long follow up to all patients.

Consider periodic monitoring of bone densitometry and of pituitary function where indicated.

Patients with Turner’s syndrome, Klinefelter’s, Kallmann’s or underlying pituitary disease will require specific follow up.

Klinefelter's syndrome

Offer genetic counselling. Follow protocol according to absent puberty as above.

Offer life long follow up.

Androgen insensitivity

Offer genetic counselling. Follow the usual protocol for absent puberty.

Offer life long follow up.

Kallmann's syndrome

Offer genetic counselling. Arrange an MRI scan of the pituitary and olfactory bulbs, and a renal ultrasound scan. 

Follow the protocol for absent puberty, and offer life long follow up. For further management see Kallmann's syndrome.

Turner's syndrome

Offer genetic counselling. Follow the treatment pathway for pubertal induction. 

For further management see Turner's syndrome.