Disorders of sexual function encompass a broad, complex array of conditions. These conditions range from chromosomal abnormalities to hormonal imbalances, psychological issues and structural defects.
Let’s first categorise some of the categories related to disordered sexual function before discussing some of them further:
- Chromosomal abnormalities
- Klinefelter syndrome
- Turner syndrome
- XYY syndrome
- Triple X syndrome
- Genetic abnormalities
- Congenital adrenal hyperplasia (CAI)
- Aromatase deficiency
- Kallmann syndrome
- Androgen insensitivity syndrome (AIS)
- 5-alpha reductase deficiency
- Swyer syndrome
- Hormonal disorders
- Hypogonadism
- Hyperprolactinaemia
- Polycystic ovary syndrome (PCOS)
- Thyroid disorders
- Psychological and psychosexual disorders
- Gender dysphoria
- Sexual dysfunction (such as erectile dysfunction, premature ejaculation, anorgasmia, sexual desire disorders, sexual arousal disorders, pain disorders)
- Paraphilic disorders (such as pedophilic disorder, voyeuristic disorder, sexual masochism disorder, sexual sadism disorder, and more)
- Developmental and structural abnormalities
- Hypospadias
- Ambiguous genitalia
- Müllerian agenesis (Mayer-Rokitansky-Küster-Hauster syndrome)
- Vascular and neurological disorders
- Diabetes-related sexual dysfunction
- Multiple sclerosis
- Spinal cord injury
- Iatrogenic causes
- Antidepressants
- Antipsychotics
- Antihypertensives
- Chemotherapeutic agents
- Lifestyle factors
- Chronic stress/anxiety
- Obesity
- Substance abuse
- Age-related conditions
- Menopause
- Andropause
The focus of this page shall be centred around chromosomal and genetic abnormalities:
CAH is a group of autosomal recessive disorders associated with impaired adrenal steroid production.
Pathophysiology
These 3 enzymes are vital for the synthesis of cortisol and aldosterone, and in rare cases androgen. In CAH these enzymes are affected and are deficient.
The 3 enzymes implicated in CAH:
- 21β-hydroxylase - this is the most common type. It makes up around 95% of CAH cases. There is impaired conversion of 17-hydroxyprogesterone to 11-deoxycortisol (a cortisol precursor). As such there is deficient cortisol production. A lack of cortisol also means there is impaired negative feedback to the pituitary. This results in adrenocorticotrophic hormone (ACTH) being uninhibited and increasing. A raise in ACTH stimulates adrenal hyperplasia and androgen precursor overproduction.
- 11β-hydroxylase - this makes up around 5% of cases. This impairs the conversion of 11-deoxycortisol to cortisol. There is an accumulation of 11-deoxycortisol and deoxycorticosterone. Deoxycorticosterone has mineralocorticoid activity which may result in hypertension and hypokalaemia.
- 17α-hydroxylase- this is rare. It involves a defect in the enzyme converting pregnenolone and progesterone which are necessary for producing cortisol and the sex steroids. This leads to cortisol deficiency and ACTH rise, but in this case there is reduced oestrogen and androgen production.
Cortisol | ACTH | Androgens | |
21β-hydroxylase | Low | High | High |
11β-hydroxylase | Low | High | High |
17α-hydroxylase | Low | High | Low |
🔢 Classification
CAH can be divided into 2 types:
- Classic - this type is more severe and is discovered at birth or in infancy. It has 2 subtypes: result in s
- Salt-wasting CAH - the most severe form. A lack of aldosterone results in excessive sodium loss through renal excretion which results in shock.
- Simple virilizing CAH - a milder form of aldosterone deficiency is less severe and there are no life threatening symptoms. However, there is an excess of androgen production which results in virilization of females and precocious puberty in boys.
- Non-classic CAH - the mildest form. It is also known as late-onset CAH as it usually doesn’t appear up until late childhood or adolescence. Symptoms may or may not be present.
😷 Presentation
Signs of classic CAH include:
- Short stature - due to early closure of the growth plates.
- Virilization of external genitalia females (males have normal genitalia at birth)
- Hirsutism and infertility in females
- Precocious puberty in males
Signs of non-classic CAH include:
- Mild virilization and menstrual irregularities in females
- Hirsutism in females
- Early development of pubic hair in males
- Accelerated growth in childhood but short stature in adolescence
Presentation of 21-hydroxylase deficiency:
- Virilization in females
- Precocious puberty and short stature in males
- Salt-wasting crisis
Presentation of 11-hydroxylase deficiency:
- Virilization in females
- Precocious puberty and short stature in males
- Hypertension and hypokalaemia
Presentation of 17-hydroxylase deficiency:
- Primary amenorrhoea in females
- Ambiguous genitalia in males
- Lack of secondary sexual development in both sexes (sexual infantilism)
- Hypertension and hypokalaemia
💡 Hyperpigmentation is a common feature across all forms of CAH as ACTH is high in all forms. ACTH’s precursor is pro-opiomelanocortin (POMC). POMC is cleaved to produce ACTH and melanocyte stimulating hormone (MSH). As the name implies, MSH stimulates melanocytes to produce melanin.
This is due to aldosterone deficiency and may present with:
- Hypotension and shock
- Hyperkalaemia and arrhythmias
- Hyponatraemia and dehydration
🧰 Management
- Hydrocortisone - to treat cortisol insufficiency.
- Fludrocortisone - to treat aldosterone insufficiency.
- Corrective surgery - for virilised genitalia.
Aromatase deficiency involves a mutation in the CYP19A1 gene that codes for the aromatase enzyme. Aromatase is responsible for peripheral conversion of androgens to oestrogens in adipose tissue, ovaries and the placenta. If aromatase is absent, there is an accumulation of androgens and deficiency in oestrogens. This causes virilization and ambiguous genitalia in females. Male infants are not affected as much with infants appearing normal but later on males may exhibit signs and symptoms.
😷 Presentation
- Tall stature
- Osteoporosis
- Hyperglycaemia
- Weight gain
- In males:
- Normal appearing infants
- Abnormal sperm production
- Tall stature
- Eunuchoid body habitus
- Bone pain and low bone density
- In females:
- Ambiguous genitalia and clitoromegaly
- Virilization
- Sexual infantilism
- Ovarian cysts
👩🍼 In pregnancy, if the fetus is aromatase deficient, the mother may also face virilization and have symptoms such as deepening of the voice, hirsutism, acne. These symptoms are resolved after paturition.
🔍 Investigations
The fetus can be predicted to be aromatase deficient if the mother displays evidence of virilization during pregnancy.
- Oestrogen levels - low
- Androgen levels - high.
🧰 Management
- Males - transdermal oestrogen. This allows for closure of the epiphyseal plates and increases bone density. It also helps regulate the glycaemic levels.
- Females
- Oral hormone replacement therapy - this allows breast development, menses, pubertal growth, and may help resolve ovarian cysts.
- Surgery - for ambiguous genitalia, clitoromegaly, and ovarian cysts.
Kallmann’s syndrome is characterised by hypogonadotropic hypogonadism (secondary hypogonadism) and anosmia.
Pathophysiology
It involves the disruption in the migration gonadotropin-releasing hormone (GnRH) neurones from the olfactory placode to the hypothalamus during embryonic development. This leads to a deficiency in GnRH as well as disturbed development in the olfactory bulbs and olfactory tracts.
Genes implicated in this genetic disorder include: KAL1, FGFR1, PROKR2 and PROK2. The inheritance pattern can be X-linked recessive (only manifesting in males), autosomal dominant or autosomal recessive (depending on the mutation involved).
😷 Presentation
- Delayed puberty
- Secondary hypogonadism
- Anosmia/hyposmia
- Cleft lip/cleft palate
- Females:
- Absent breast development in females
- Primary amenorrhoea
- Males:
- Cryptorchidism in males
- Lack of facial and body hair in males
- Absent muscle bulk
🔍 Investigations
- Serum testosterone in males - <300ng/dL.
- Serum oestrogen in females - typically low.
- GnRH, LH and FSH - this helps differentiate between primary and secondary hypogonadism:
- MRI of the brain - to assess the olfactory bulbs.
- Olfactory function tests
- Genetic testing
GnRH | LH | FSH | |
Primary hypogonadism | High | Low | Low |
Secondary hypogonadism | Low | Low | Low |
🧰 Mangement
- Testosterone injections or hCG injections
AIS is an X-linked recessive condition resulting in partial or complete insensitivity to androgens.
Pathophysiology
Mutations to the AR gene on the X-chromosome leads to defective androgen receptors or complete absence of them. This means there is resistance to testosterone in end-organs. As such the patient would have a male karyotype (46,XY) but may be phenotypically variable depending on the severity.
Complete AIS (previously termed testicular feminisation syndrome) results in a female external phenotype while partial AIS results in phenotypes that range from predominantly male to predominantly female.
😷 Presentation
- Complete AIS:
- Female external genitalia and physique - this includes breast development.
- Blind-ended vaginal pouch, uterine agenesis and fallopian tube agenesis - as the testes still produce anti-Müllerian hormone in embryonic development due to the 46,XY genotype.
- Cryptorchidism
- Absent or sparse pubic hair
- Primary amenorrhoea - the patient may present with this as the primary complaint when in fact they do not have the internal reproductive structures for menstruation.
- Partial AIS has varying phenotypic presentations depending on the degree of androgen insensitivity.
🔍 Investigations
- Karotyping - 46,XY karyotype.
- Testosterone levels - upper end of normal or elevated.
- Pelvic ultrasound or MRI - to assess internal pelvic structures. Absence of uterus and fallopian tubes may be seen. The location of the undescended testes may be identified too.
🧰 Management
- Gender identity counselling - although this is more nuanced than simply saying the child should be raised as a girl, specialists advise that children with complete AIS be raised as girls due to their genitalia, lack of testosterone response and the fact that almost all tend to identify as a female when they’re older. The discussions with the specialist team advise parents about the estimation of the child’s physical sex development. The discussion is primarily with parents early on but as the individual grows older they can take over the discussions with the doctors. With PAIS it can be substantially trickier as the phenotype can vary so much. Patients are entitled to specialist advice with regards to development and gender identity issues that may arise. Most children with PAIS remain with the gender they have been raised with but some feel as though this does not represent who they are and they may opt for gender affirmation later in life.
- Orchidectomy - adults with CAIS may have their internal testicles removed as it poses a risk of cancer if left in. It is done after puberty as the testicle produce hormones that help with female development without the need for hormonal treatments. If they are removed prior, hormonal treatment will be needed.
- Vaginal surgery - as girls with AIS tend to have a shorter vagina which can make penetration difficult during sexual intercourse. This is also delayed until after puberty.
- Breast reduction surgery - for boys with PAIS.
- Hormonal therapy - for women with CAIS who have had an orchidectomy too prevent osteoporosis and menopausal symptoms. It also aids in the development of a female body shape.
5-ARD is an autosomal recessive genetic disorder that affects male sexual development due to issues relating to the gene encoding for the 5-alpha reductase type 2 enzyme.
Pathophysiology
5-alpha reductase type 2 is an enzyme responsible for the conversion of testosterone into dihydrotestosterone (DHT). DHT is essential for the development of male sexual characteristics during embryonic development. In 5-ARD there is a deficiency in this enzyme which means that DHT does not form. As such, the baby has a 46,XY karyotype but is born with ambiguous genitalia or predominantly female genitalia. However, the internal reproductive organs are that of a male.
During puberty, testosterone levels increase and this can lead to virilization (development of male physical characteristics) because testosterone itself at higher levels may induce secondary sexual characteristics to be developed.
The gene implicated in 5-ARD is the SRD5A2 which is located on chromosome 2.
😷 Presentation
- Female external genitalia at birth - although the vagina may simply be a blind-ended pouch.
- Male internal reproductive organs - the prostate may be underdeveloped commonly.
- Development of secondary male sexual characteristics during puberty - this includes testicular descent and phallic growth.
🔍 Investigations
- Testosterone-DHT ratio - measured after hCG stimulation. The individual may show an increase in the ratio of testosterone to DHT.
- Genetic testing - assessing for mutations of the SRD5A2 gene.
🧰 Management
Once again the management is nuances depending on the phenotypic expression of the child and also how they have been raised as well as how they identify.
If the child is to be raised as a female, orchidectomy would need to be done prior to puberty and virilization. This would be followed by external genitalia reconstruction and vaginoplasty later on.
If the child is raised as a male then the corrective surgery would depend on the phenotypic expression of the child. The main considerations include the functionality and developmental size of the penis. Surgeries may include hypospadias correction and urethra reconstruction.
Parents may seek assistance and support and take adequate time to decide the gender of the child and potential treatment options.
Swyer syndrome, also known as 46,XY gonadal dysgenesis, is a condition affecting 46,XY (male karyotype) individuals. It presents with female external genitalia due to defects in the development of the testes during embryonic development.
Pathophysiology
Normally in 46,XY individuals, the SRY gene on the Y chromosome initiates the development of the testes early on in development. The testes then produce anti-Müllerian hormone (AMH) which causes regression of the Müllerian ducts. This prevents development of female internal reproductive organs.
In Swyer syndrome, there is a mutation on the SRY gene or the MAP3K1 gene that results in impaired testicular development. This means there is inadequate testosterone production and subsequently incomplete virilization. This may result in female or ambiguous external genitalia. The absence of AMH also allows the Müllerian ducts to develop into the female internal reproductive organs.
As the testes do not develop, the ovaries also do not develop from the undifferentiated gonadal ridge. Thus, despite the female phenotype there will be primary amenorrhoea and infertility.
😷 Presentation
- Testicular agenesis
- Female external genitalia as well as vagina and uterus present - there will also be ovarian agenesis.
- Primary amenorrhoea - due to the absence of ovaries despite internal reproductive organs being present. This may be the presenting symptom typically.
- Streak gonads - underdeveloped gonads that do not produce sex hormones during development.
🔍 Investigations
- Karyotyping - 46,XY karyotype.
- Pelvic ultrasound or MRI - to assess the internal reproductive structure and look for the absence of ovaries.
- Hormonal assessment - testosterone levels are low, LH and FSH may be high due to the lack of negative feedback from sex steroids.
🧰 Management
- Hormonal replacement therapy - to induce puberty and secondary sexual characteristics. This includes oestrogen and progesterone. It also helps prevent osteoporosis in later life.
- Removal of streak gonads - as their presence increases the risk of a gonadal tumour.
- Fertility counselling - although women with Swyer syndrome are infertile, they may become pregnant and carry to term with the use of donated eggs.