Idiopathic hypogonadotropic hypogonadism: a rare cause of primary amenorrhoea in adolescence—a review and update on diagnosis, management and advances in genetic understanding.

Abstract

Idiopathic hypogonadotropic hypogonadism (IHH) refers to a family of genetic disorders that affect the production and/or action of gonadotropic-releasing hormone, resulting in reduced serum levels of sex steroids. This condition has a prevalence of 1–10 cases/100 000 births and is characterised by the absence of spontaneous pubertal development. In women, the condition is characterised by the onset of normal adrenarche, with the absence of thelarche and menarche. Pubertal induction for breast development and uterine growth with oestradiol, and sequential maintenance of a normal menstrual cycle and adequate oestrogen for bone health, with an oestrogen and progesterone, is considered first-line treatment. Pregnancy can be achieved in patients who have received and responded to treatment with ovulation induction with exogenous gonadotrophins. Advances in genetic testing have led to increased research and understanding of the underlying genetics of IHH with gene mutations described in up to 50% of all IHH cases.

Background

Idiopathic hypogonadotropic hypogonadism (IHH) refers to a family of genetic disorders that affect the production and/or action of gonadotropic-releasing hormone (GnRH), resulting in reduced serum levels of sex steroids. This rare condition has a prevalence of 1–10 cases per 100 000 births,¹ and is characterised by the absence of spontaneous pubertal development. IHH may be associated with anosmia, referred to as Kallmann syndrome, or otherwise classified as normosomic IHH. As the condition predominantly affects men, with a reported ratio of 4:1,² there is a paucity of literature describing the condition in women. In women, the condition is characterised by the onset of normal adrenarche, with the absence of thelarche and menarche. It is diagnosed in 5% of all women with primary amenorrhoea, of which the reported prevalence is 0.1%–0.3%.³

Advances in genetic testing have led to increased research and understanding of the underlying genetics of IHH. Mutations in genes that contribute to normal development, migration and secretion by GnRH neurons have been described in up to 50% of all IHH cases, and include ANOS1 (KAL1), FGF8, FGFR1, FGF17, IL17RD, DUSP6, SPRY4, FLRT3, KLB, PROK2, PROKR2, HS6ST1, CHD7, WDR11, SEMA3A, SEMA3E, IGSF10, SMCHD1, CCDC141 and FEZF1.⁴

Case presentation

An adolescent aged 15 years and 5 months was reviewed by her paediatrician with concern regarding primary amenorrhoea and delayed thelarche. Preliminary laboratory screening found undetectable serum gonadotrophin levels and oestradiol levels, with no evidence of other disease. Her karyotype was confirmed to be 46 XX. A pelvic ultrasound (US) and MRI that had been performed had found the absence of a uterus and ovaries, and a rudimentary vagina approximately 1.8 cm in length, a normal renal tract, and was reported as ‘suspicious for Mayer-Rokitansky-Kuster-Hauser syndrome’. MRI brain found no abnormality of the pituitary or hypothalamus.

The adolescent was referred, at the age of 15 years and 6 months, to the Adolescent Endocrinology, and Paediatric and Adolescent Gynaecology (PAG) teams at the tertiary Children’s Hospital for investigation and management.

Further clinical history did not reveal any suggestion of pituitary disease, chronic disease, excessive exercise or eating disorder, and there was no family history of constitutional delay. On examination, her findings were as follows: well appearance, height of 166.7 cm, weight of 55.9 kg, body mass index 20.1 kg/m² and no stigmata of disease. She had normal pubic hair development to Tanner stage 3, but no breast development (Tanner stage 1). The external genitalia were normal, with a patent vaginal orifice. A Q-tip cotton swab was able to be passed to demonstrate a normal vaginal length of 6 cm, hence not consistent with the MRI report which had raised a possible diagnosis of Mayer-Rokitansky-Kuster-Hauser (MRKH).

Investigations

Repeat blood investigations found undetectable follicle-stimulating hormone (FSH) and luteinising hormone (LH), and oestradiol. Cortisol, ACTH and IGF-1 were normal. Other investigations including full blood count, serum biochemistry, thyroid function, prolactin and testosterone were all normal. Her karyotype had already been performed and was 46 XX. An autoimmune screen was performed to exclude autoimmune premature ovarian failure. The screen which included antiovarian antibodies, anticardiolipin antibodies, antinuclear antibodies and lupus anticoagulant was negative. An Anti-Mullerian hormone (AMH) was performed with a level of 13.7 pmol/L (reference 10–30), suggesting the presence of ovaries with functional potential.

A repeat tertiary hospital Pelvic MRI aged 15 years and 9 months found a small uterus measuring 30 × 10 × 13 mm with a cervical length of 13 mm and small ovaries bilaterally (figure 1). An MRI was chosen over an US, as a more sensitive tool for assessing Mullerian structures.

Figure 1.

Pelvic MRI aged 15 years 9 months showing a small uterus measuring 30 × 10 × 13 mm with a cervical length of 13 mm and small ovaries bilaterally.

A baseline bone mineral density (BMD) test prior to commencing estradiol was low for chronological age but normal for bone age and a plan was made for a repeat BMD in 2 years from commencement of the combined contraceptive pill (CCP). The BMD was performed as adolescents with delayed or reduced estradiol are at risk of osteopenia and/or osteoporosis and may benefit from early intervention.

Treatment

A working diagnosis of IHH was made. Pubertal induction was initiated with the estradiol transdermal patch (Climara, Bayer) at the age of 15 years 10 months. The adolescent was started on ¼ of a 25 μg patch, which was increased to ½ patch after 3 months and then a whole patch after 6 months.

On review at 16 years and 7 months, her breasts development had progressed to Tanner stage 3, and the dosage of the estradiol patch was increased to 50 μg. A repeat pelvic MRI at age 17 years and 2 months found an increase in the size of the uterine body to 37 × 22 × 39 mm with cervical length 19.5 mm and normal sized ovaries bilaterally containing multiple antral follicles (figure 2).

Figure 2.

A repeat pelvic MRI at age 17 years and 2 months found an increase in the size of the uterine body to 37 × 22 × 39 mm with cervical length 19.5 mm and normal sized ovaries bilaterally containing multiple antral follicles.

Following breast development to Tanner stage 5 at 17 years and 6 months, the estradiol transdermal patch was ceased, and she was commenced on a CCP containing 30 μg ethinylestradiol and 150 μg levonorgestrel. Menarche occurred soon after the CCP was commenced, and the adolescent opted to have 3 monthly menstrual cycles for convenience.

To exclude that the adolescent did not have an extreme form of constitutional delay rather than hypogonadotropic hypogonadism, at the age of 18 years the CCP was withheld for 3 months and a GnRH (Lucrin) stimulation test was performed. The patient had an only mild partial response with a peak LH level of 2.6, a peak FSH of 5.7 and no increase in oestradiol level. She was found to have ongoing idiopathic gonadotrophin deficiency and recommenced on the CCP.

At age 18 years, she was reviewed by a Reproductive Endocrinology and Fertility specialist regarding future fertility. The patient was counselled regarding both the need for FSH and LH stimulation to achieve ovulation for pregnancy and/or oocyte retrieval for in vitro fertilisation (IVF). There was not thought to be an indication for oocyte cryopreservation at this stage; however, the option of oocyte retrieval and storage in her 20s for optimising changes of IVF has been offered. Given that up to 50% of apparently hereditary cases of IHH are associated with genetic mutations,⁴ the patient was counselled that she may benefit from genetic testing to better understand the possible implications of transmission to offspring. She was referred to the Genetics Department for review, and after further counselling, the patient decided to proceed with genetic testing with a 13 gene panel through Fulgent Genetics (see below). In this patient’s case, her test was negative, and a mutation was not detected. This patient has been left on the registry to be screened again in the future for any emerging gene tests.

With respect to her psychological well-being, the adolescent was provided with supportive counselling at each review in the PAG clinic and was also seen by a psychologist. She was always accompanied by her mother, who was very supportive and involved in her care. The adolescent was also referred to internet support groups and global communication networks for IHH.

Outcome and follow-up

The adolescent has had good outcome, with appropriate pubertal induction as an adolescent, resulting in normal breast and uterine development, and psychological health. The adolescent continues to be reviewed annually by the PAG team and is currently aged 21 years of age. She understands the need for continued hormone replacement until at least the age of 45 years.

Discussion

Puberty and primary amenorrhoea

Normal pubertal development is the result of aptly timed biological changes involving the increased release of androgens by adrenal glands and maturation of the hypothalamic–pituitary–ovarian (HPO) axis. Stimulated release of GnRH triggers a domino effect with increased secretion of gonadotrophins FSH and LH. This secretion, in turn, encourages gonadal maturation and secretion of sex steroid hormones: oestrogens, progesterone and androgens.⁵

Primary amenorrhoea is defined as the absence of menses by age 16 in the presence of normal growth and secondary sexual characteristics, or as the absence of menses by age 14 where onset of puberty has not occurred.⁶ It can occur when there is a disorder affecting any part of the HPO axis including the hypothalamus, anterior pituitary, ovaries or outflow tract. The reported prevalence of primary amenorrhoea ranges from less than 0.1% to 0.3%.

The differential diagnosis of primary amenorrhoea in adolescents presents a wide spectrum of conditions (table 1). Chromosomal abnormalities causing gonadal dysgenesis (45X and variants, 46XX, 46XY) represent 43%, followed by Mullerian agenesis or other Mullerian anomalies 19%, physiological delay of puberty 14%, polycystic ovarian syndrome 7%, GnRH deficiency 5%, disorders of the hypothalamus or pituitary such as hypopituitarism, hyperprolactinoma or other pituitary tumours or craniopharyngioma 6%, weight loss and/or extreme exercise and/or anorexia nervosa 2%, congenital androgen insensitivity syndrome 1%, classic and non-classic congenital adrenal hyperplasia 1% and Cushing’s syndrome and thyroid disease 2%.⁷ Investigation of primary amenorrhoea should be individualised based on patient presentation and symptomatology and clinical examination, but should consider investigations listed in box 1.

Table 1.

Differential diagnosis of primary amenorrhoea in adolescents

Differential diagnoses of primary amenorrhoea	Example
Gonadal dysgenesis	45XO, 46XX (POF), 45X and variants, 46 XX, 46XY
Mullerian agenesis or anomaly	MRKH, vaginal septum, imperforate hymen
Constitutional delay
Polycystic ovarian syndrome
GnRH deficiency	Familial, chronic systemic illness
Eating disorders, stress, excess exercise
Pituitary disease	Hyperprolactinaemia, pituitary tumours, hypopituitarism
Other CNS disease	Craniopharyngioma
Adrenal disease	Cushing’s syndrome, congenital adrenal hyperplasia (CAH), non-classical CAH (NCAH) androgen secreting tumour
Thyroid dysfunction
Androgen insensitivity syndrome

CNS, Central Nervous System; GnRH, gonadotropic-releasing hormone; MRKH, Mayer-Rokitansky-Kuster-Hauser.

Box 1. Investigation of Primary amenorrhoea in adolescents.

Initial investigations

• Beta human chorionic gonadotropin (bHCG)

• Full blood count (FBC), chem-20

• Luteinising hormone, follicle-stimulating hormone, oestradiol, progesterone

• Prolactin

• Thyroid stimulating hormone (TSH) and T4

• Serum 17-hydroxyprogesterone (17-OHP) (follicular phase, morning)

• Serum testosterone, sex hormone binding globulin

• Dehydroepiandrosterone (DHEAs)

• Karyotype

• Pelvic US +_ MRI

• Bone age

Targeted investigations

• Autoimmune screen if Premature ovarian failure (POF) suspected

• Serum cortisol (morning)

• Human growth hormone, IGF-1

• Adrenocorticotropic hormone (ACTH) stimulation test to exclude non-classical congenital adrenalhyperplasia

• Dexamethasone suppression test to exclude Cushing’s syndrome

• MRI adrenals to detect mass or tumour

• MRI pituitary to detect mass or tumour

• Leuprorelin stimulation test

• Progestin challenge test

Idiopathic hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism refers to the absence of spontaneous pubertal development resulting from reduced GnRH and/or gonadotrophin release. In cases where there is no apparent cause, the condition is referred to as IHH and can be subdivided as congenital or acquired.² IHH is distinct from acquired hypogonadotropic hypogonadism. The latter is often associated with hypothalamic amenorrhoea (‘functional amenorrhoea’) caused by eating disorders, excessive exercise or stress, second, destructive processes such as tumours, radiation, trauma or infiltrative disease, and third, disorders of the anterior pituitary.⁸ IHH has an incidence of 1–10 cases per 100 000 births. Kallmann syndrome (1:120 000 women), a form of IHH featured by anosmia, is caused by abnormal migration of GnRH and olfactory neurons.⁹

In women, the condition clinically manifests in early adolescent years. Patients with IHH usually experience pubarche as there is normal androgen production by adrenal glands. However, as the primary abnormality is a defect in the hypothalamic or pituitary region, this results in the failure of the HPO axis to stimulate steroidogenesis and production of oestrogen and progesterone in the ovaries, leading to absent breast development and menstruation. Consequently, patients with IHH will present with an absence of, or minimal, breast development by age 13 and primary amenorrhoea.⁴ The condition can be difficult to differentiate from constitutional delay in growth and puberty. Constitutional delay reportedly accounts for one-third of pubertal delay in girls, and some have suggested similar underlying pathophysiology between the two conditions with a shared genetic basis.¹⁰ For example, variants in genes such as TAC3 and TACR3 have been found shared by individuals with IHH or constitutional delay in the same family.¹¹ Hence, accurate diagnosis can be difficult to achieve.

The diagnosis of IHH is made by low serum levels of gonadotrophins and sex steroids with normal radiographic imaging of the hypothalamic–pituitary region, and the exclusion of differential diagnoses listed on table 1.⁵ To confirm the diagnosis, a GnRH (Lucrin) stimulation test may be performed.¹² Although the diagnosis is largely clinical, genetic testing may be beneficial in the detection of common genetic defects, which can guide counselling. Negative molecular testing does not rule out a possible diagnosis as many associated genes remain unknown.

As IHH predominantly affects men, there is a paucity of literature describing the condition in women and its long-term implications for fertility and pregnancy. Few case reports have been published on female patients. Genetic analysis, exogenous hormone replacement therapy and ovulation induction are prevailing themes in the literature. Close monitoring and follow-up of patients with IHH in a multidisciplinary setting is of crucial importance as the rarity of this condition can lead to diagnostic delays, and delays in management. Failure to diagnose the condition in the adolescent period can lead to a missed opportunity for pubertal induction for adequate breast and uterine development. This can have adverse physical, psychological and fertility implications. For example, in one case report, a 27-year-old woman with primary amenorrhoea and pubertal failure was initially misdiagnosed with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome following pelvic ultrasonography at age 17 years that revealed no uterus or ovaries. Unfortunately, no further investigations, such as a basic hormone profile, were performed or treatments implemented during the ensuring decade. Diagnostic laparoscopy and MRI a decade later found a tubular hypotrophic uterus with bilateral normal fallopian tubes and ovaries, and vagina.¹³ If further investigations had been conducted earlier, she would not have been mislabelled as having MRKH, she may have experienced a more fulfilling adolescent period and had options for fertility.

Management of IHH

The primary treatment goals for female patients with IHH are to achieve normal breast and uterine development, and to gain the ability to conceive and maintain a pregnancy. There is evidence for the use of oestrogen replacement therapy in younger patients (less than 20 years of age) with primary amenorrhoea due to hypogonadism.^{14 15} Estradiol, in the form of patches (Climara, Bayer) or oral formulation (Progynova, Bayer), is most commonly used for pubertal induction. It is continued until breast development reaches Tanner stage 4–5 and adequate uterine growth has been established.¹⁶ In this case, our patient was commenced on estradiol patches (Climara 25 μg/24 hours, Bayer), starting with ¼ patch and increasing by another ¼ patch every 3 months, then progressed to a 50 μg/24 hours patch. The response to treatment can also be assessed by changes in uterine cross-sectional area and uterine maturity (uterine length by fundocervical ratio), as it appears dependent on the total dose of oestrogen replacement and aetiology of primary hypogonadism.¹⁵ Adolescents may be then commenced on a CCP containing ethinylestradiol to induce menstruation and provide long term estrogen–progestin replacement. We typically commence a second generation CCP, continuing ethinylestradiol and levonorgestrel. Alternative regimes for hormonal management of pubertal induction, with other options including a daily estradiol and with cyclical progestins for 12 days per month. Women will require adequate hormone replacement therapy until the natural age of menopause to maintain healthy oestrogen and progesterone levels.

In young women with IHH, early referral to a fertility specialist may allay anxiety regarding future fertility and provide comprehensive education on the options available to them when they are ready to conceive. Pregnancy can be achieved in patients who have received and responded to treatment. Ovulation induction with exogenous gonadotrophins is the first-line reproductive option. A retrospective single-centre cohort study of 138 women with IHH over 1990 to 2016 found that in the 16 women who were seeking to conceive and underwent either pulsatile GnRH treatment, ovulation induction or IVF and embryo transfer (IVF-EF), the clinical pregnancy rate was 81.3% and the live birth rate was 68.8%.¹⁷ In two case reports, both women were able to successfully complete pregnancy, one following ovulation induction with exogenous gonadotropin aged 35, and the other by IVF-EF aged 28.^{18 19}

Low levels of endogenous oestrogen put patients with IHH at risk of osteoporosis from a young age. Adolescents should be counselled regarding the need for regular exercise, adequate calcium and vitamin D intake, and avoidance and/or cessation of smoking. Exogenous oestrogen replacement is important for building and maintaining peak bone mass.²⁰ A baseline DEXA scan for bone density should be performed, and if osteopenia or osteoporosis is present, it should be repeated 2–3 years after commencement of oestrogen to ensure normal bone density has been achieved.

Addressing the psychological well-being of female adolescents with IHH is of high clinical importance in providing comprehensive holistic care. Psychological support may be provided by involved clinicians at each appointment, and through referral to a psychologist with an interest in women’s health. Internet support groups and global communication networks for IHH can be very helpful for patients with rare conditions.

Genetics of IHH

Over the past decade, an array of genes have been identified that contribute to normal development, migration and production and secretion by GnRH neurons. Mutations in several of these genes have been described in patients with hypothalamic amenorrhoea, although full molecular pathogenesis of the disorder is unclear.²¹ A recent review by Topaloglu¹⁴ reported that identifiable genetic defects account for up to 50% of all IHH cases. Most genetic defects are sporadic however; they can be associated with autosomal dominant, and sometimes sex-linked or autosomal recessive, patterns of inheritance. Genes associated with Kallmann Syndrome include ANOS1 (KAL1), FGF8, FGFR1, FGF17, IL17RD, DUSP6, SPRY4, FLRT3, KLB, PROK2, PROKR2, HS6ST1, CHD7, WDR11, SEMA3A, SEMA3E, IGSF10, SMCHD1, CCDC141 and FEZF1. In particular, screening for specific genes has been suggested in cases where there are certain clinical features, such as KAL1 for synkinesia, FGF8/FGFR1 for dental agenesis or digital bony abnormalities and CHD7, SOX10 for hearing loss.²² Genes associated with normosmic IHH appear to play a more intimate role with the HPO axis and study of these mutations have found reversible cases of IHH with GnRH administration. Interestingly, a mutation in the CHD7 gene may cause either normosmic IHH or Kallmann syndrome, thereby blurring the distinction between these disorders. Genes linked with disorders of the GnRH pulse generator include TAC3, TACR3, KISS1, KISS1R, GNRHR, and GNRH1. Of these, GNRHR and TACR3 mutations were found to be the two most common genetic mutations in one study, affecting 13 of 22 families who fit the normosmic IHH phenotype (absence of spontaneous puberty by age 13 in girls and age 14 in boys, bone age of 11.5 years or greater, and low sex hormone concentrations in the setting of low gonadotrophin levels).²³ Surprisingly, the other obvious candidate gene GNRH1 has only been identified as a definitive cause of IHH in one of 310 patients.²⁴ Administration of pulsatile GnRH has been reported to reverse cases of IHH where there are inactivating mutations is in GNRH1.²⁵ Research of the KISS1 gene and its peptide hormone kisspeptin, a regulator of GnRH secretion, has also found promising treatment options in the form of exogenous administration (kisspeptin-54 and kisspeptin-10) to patients with hypogonadotropic hypogonadism, polycystic ovarian syndrome, hypogonadism associated with type 2 diabetes mellitis, early or delayed puberty, and those with fertility disorders requiring induction of ovulation.²⁶ Other normosmic IHH associated genes include NROB1 (DAX1), NR5A1, SRA1, HESX-1, LHX3, PROP-1, SOX2, GNRHR, FSHB, LHB, LEP, LEPR, PC1, PNPLA6, RNF216, OTUD4, STUB1, POLR3A, POLR3B, RAB3GAP1, RAB3GAP2, RAB18, TBC1D20 and DMXL2.

The increasing use of sequencing technologies such as next generation sequencing has enabled greater insight into oligogenic inheritance. Fulgent Genetics (California) has a Hypogonadotropic Hypogonadism Panel which examines 13 genes: ANOS1 (KAL1), CHD7, FGF8, FGFR1, GNRH1, GNRHR, KISS1, KISS1R, NR0B1, NSMF, PROKR2, TAC3 and TACR3.²⁷ Testing for genetic defects may provide confirmation of the diagnosis of IHH and may assist in genetic counselling regarding patterns of inheritance and implications for offspring.

Learning points.

• Idiopathic hypogonadotropic hypogonadism (IHH) is a rare disorder that may present as delayed thelarche and primary amenorrhoea in the female adolescent.

• Improved awareness of this condition is essential to facilitate early detection, diagnosis and treatment, to achieve a good outcome, including reproductive potential.

• First line management for women with IHH is induction of puberty with sequential long-term oestrogen–progestin replacement.

• Early multidisciplinary holistic and complementary care involving the general practitioner, paediatrician, adolescent endocrinologist, adolescent gynaecologist, fertility specialist, psychologist and geneticist all play a significant role in achieving successful outcomes.