In this article we will discuss about the syndromes involving hormonal abnormalities in humans.
True hermaphrodites are individuals who have both ovarian and testicular tissue. This occurs extremely rarely. Conditions involving hormonal abnormalities that result in ambiguities of the genitalia are more common, although their precise frequency is unknown.
A generous estimate in North America and Europe would probably be that somewhere in the region of 1 in 5000 to 1 in 10,000 births involves an intersex condition characterized by dramatic abnormality of the external genitalia. If less dramatic abnormalities, such as hypospadias or gynecomastia are included, estimates could reach as high as 1 in 100 individuals.
Most of our information on the human consequences of early hormonal perturbations has come from the more dramatic, but rarer, causes of genital ambiguity, since some of these are known to involve hormonal abnormalities of prenatal onset.
The primary sources of information have included:
(1) XX individuals exposed to high levels of androgens prenatally because of congenital adrenal hyperplasia (CAH);
(2) XY individuals exposed to lower than normal levels of androgens prenatally because their cells have deficient or defective androgen receptors (androgen insensitivity syndrome-AIS);
(3) XY individuals exposed to reduced androgens prenatally because they are deficient in enzymes needed to produce particular androgens from precursor hormones.
Some other conditions that involve prenatal hormonal abnormality, usually without ambiguity of the external genitalia at birth, have also been studied.
These include:
(4) XY individuals with idiopathic hypogonadotrophic hypogonadism (IHH), a syndrome involving deficiency in the hypothalamic hormones that promotes the production of testicular hormones.
(5) XX or XO individuals exposed to lower than normal levels of ovarian hormones prenatally, because their second X chromosome is absent or imperfect, resulting in- ovarian regression (Turner syndrome).
A third set of conditions involves XY individuals who are reassigned to the female sex early in life, because of problems with the appearance of their external genitalia. Thus, their prenatal hormone environment was that of a normal male but contrasts with their female sex of rearing.
These conditions include:
(1) Cloacal exstrophy;
(2) Penile agenesis (aphallia); and
(3) Ablatio penis.
i. Congenital Adrenal Hyperplasia:
Congenital adrenal hyperplasia (CAH) is an autosomal, recessive disorder that results in overproduction of androgen, beginning prenatally. The underlying problem is a deficiency in enzymes needed to produce adrenal steroids. In 90% of cases the deficient enzyme is 21-hydroxylase (21-OH).
In this and most other forms of CAH, the negative feedback system detects the low levels of Cortisol and the adrenal attempts to compensate by producing additional metabolic precursors to it. Because of the blockage in Cortisol production, however, these precursors are shunted into the androgen pathway, resulting in an overproduction of adrenal androgens, as well as progesterone and 17-hydroxyprogesterone.
Androgen levels in female fetuses with CAH are in the range of normal males and girls with the disorder are typically born with some degree of genital virilization. In some cases the virilization is so severe that the girls are mistaken for boys at birth and reared as such. Typically, however, the girls are diagnosed with CAH near the time of birth based on genital ambiguity, and they are assigned and reared in the female sex.
They are treated with hormones to regulate the postnatal hormone milieu, and their genitalia are feminized surgically. The incidence of CAH caused by 21-OH deficiency in Europe and the United States has been estimated at between 1 in 5000 and 1 in 15,000 births, occurring in both girls and boys.
Boys appear to have normal levels of androgens prenatally, and are not born with genital ambiguity. As a consequence, their condition is usually detected because of salt-losing crises caused by aldosterone deficiency. This typically occurs within a few weeks of birth, but in some cases affected boys are not identified until the elevated adrenal androgens induce precocious puberty in early childhood.
ii. Androgen Insensitivity Syndrome:
Androgen insensitivity refers to a deficiency in the ability of androgen receptors to respond to the hormones, testosterone and DHT. This insensitivity can be complete (CAIS) or partial (PAIS). Both disorders are transmitted as X-linked, recessive traits, and thus occur predominantly in genetic males.
Individuals with CAIS appear female at birth, despite an XY chromosome complement, and typically are raised as girls with no suspicion of the underlying disorder. At puberty the breasts develop under the influence of estrogen derived from testicular androgen. Typically the disorder is detected when menstruation fails to occur, because of the lack of feminine internal reproductive structures.
Physical appearance in PAIS varies enormously, ranging from essentially that of a CAIS individual to uncomplicated hypospadias, infertility, or even gynecomastia in an otherwise healthy-appearing male. Estimates of the incidence of CAIS vary enormously, although it appears to be rarer than CAH. The incidence of PAIS is not known, perhaps because its milder manifestations go undetected.
iii. Deficiencies in Enzymes Needed to Produce Androgens:
These deficiencies are transmitted as autosomal, recessive traits. They are rare in the general population, but can occur frequently in populations where inbreeding is common. In one area of the Dominican Republic, the incidence of 5αR has been estimated at 1 in 90 males. The enzyme 5αR converts T to DHT, and patients deficient in the enzyme have low levels of DHT but normal to high levels of T.
Because DHT is needed for normal virilization of the external genitalia prenatally, 5αR deficiency results in female-appearing or ambiguous genitalia at birth, and individuals with the disorder usually are assigned and reared as girls. High levels of testosterone and DHT derived from it at puberty however, cause virilization, including growth of the phallus and scrotum, deepening of the voice and development of male-typical musculature.
The enzyme 17βHSD is needed to produce T from its immediate precursor, androstenedione. Patients deficient in this enzyme have low levels of T and DHT, but elevated levels of androstenedione. The natural history of 17PHSD is similar to that of 5aR deficiency.
The genital appearance at birth is feminine or ambiguous, but physical virilization occurs at puberty. In populations where these disorders are common they sometimes have descriptive names, such as guevedoce, geuvote (penis at 12 years of age), or machihembra (first woman, then man) or Turnim Man.
iv. Idiopathic Hypogonadotrophic Hypogonadism:
Individuals with IHH have low levels of pituitary gonadotropins or their hypothalamic releasing factor. As a consequence, their gonads lack sufficient stimulation to produce normal levels of hormones. The disorder can occur after puberty, or congenitally. If the disorder is congenital, it is usually detected when the child does not undergo normal puberty.
Males with congenital IHH usually have normal appearing genitalia at birth, perhaps because maternal gonadotropins stimulated their testes to produce hormones prenatally. Thus, it cannot be assumed that their hormone levels are lower than normal before birth. However, beginning at birth, and perhaps to some extent before, their levels of testicular hormones would be lower than in normal males.
v. Turner Syndrome:
Turner syndrome (TS) results from an absent or imperfect second X chromosome, and appears to involve a random genetic error. In 50 to 60% of cases the second X chromosome is entirely missing. Other cases involve mosaicisms or abnormalities of the second sex chromosome.
TS occur in approximately 1 in 2000 to 1 in 5000 live female births in North American and Western Europe. The external genitalia are female, but in the majority of TS girls, the ovaries regress sometime after the third month of gestation, impairing or eliminating their ability to produce hormones.
The syndrome has several stigmata, including short stature, skeletal growth disturbances, cardiovascular and renal abnormalities, otitis media, primary gonadal failure, absence of secondary sexual characteristics, and infertility. Short stature is universal in TS, and over 90% of affected females experience primary gonadal failure and infertility, but other stigmata vary dramatically from individual to individual.
vi. Cloacal Exstrophy:
Cloacal exstrophy is a severe defect of the ventral abdominal wall. It involves abnormalities and insufficiencies in the urinary and bowel systems that until 1960 were universally fatal. Now, many children born with this syndrome survive. Cloacal exstrophy occurs in approximately 1 in 200,000 to 1 in 400,000 births, and is more common in XY than XX individuals.
In XY individuals, the testes appear histologically normal but are typically undescended, and the penis is usually either absent or represented as two separate and incomplete structures. Even when present as a single structure, the penis typically is small and poorly formed. In XX individuals there are also abnormalities of the genitalia.
Because of this, most XX and XY patients with cloacal exstrophy are surgically feminized and assigned and raised as females. Those who are XY were exposed to male-typical levels of testicular hormones prenatally and neonatally, until surgical removal of the testes.
vii. Penile Agenesis (Aphallia):
In penile agenesis (aphallia), an XY individual is born without a penis, despite the presence of a normal scrotum and functioning testes. The causes of the condition are unknown, although it is usually associated with abnormalities of the urinary and gastrointestinal tracts.
Estimates of its incidence range from 1 in 50,000 to 1 in 10- 30 million, and mortality is high. As a result there are very few individuals with aphallia. However, those who do survive are often surgically feminized and reared as girls. Like XY individuals with cloacal exstrophy, their prenatal and early neonatal hormonal milieu would resemble that of healthy male fetuses.
viii. Ablatio Penis:
In rare instances accidents can cause severe damage or even complete ablation of the penis in an otherwise healthy infant. In some such cases, XY infants have been reassigned as female, surgically feminized, and reared as girls. They would have been exposed to normal male levels of testicular hormones prenatally and postnatally until the time when the testes were removed.