Gonadal Differentiation External genitalia abnormalities

Sex & Gender Differentiation and Brain Sex

 Gonadal Differentiations External genitalia abnormalities  Brain Sex Puberty

    In males, the external genitalia may fail to develop for a number of the above reasons, and the phallus may be underdeveloped, leading to hypospadias. In hypospadias, the urethra often fails to reach the end of the phallus or penis, and urine exits from the base of the penis.

    In females, the external genitalia may be virilized, giving a masculine appearance. This is most commonly seen in a condition known as congenital adrenal hyperplasia. In this condition, an enzyme defect in the adrenal gland-usually 21-hydroxylase deficiency - prevents the fetal adrenal gland from producing the production of cortisol means that the feedback mechanism on the hypothalamus leads to an elevation of adrenocorticotrophic hormone (ACTH).

    This in turn stimulates the adrenal gland to undergo a form of hyperplasia, and the excessive production of steroid precursors (17-hydroxyprogesterone) means that the adrenal gland produces excessive amounts of androgen This androgen enters the fetal circulation and impacts on the developing cloaca, thereby leading to virilization . 

    The female child is then born with a degree of phallic enlargement, and the lower part of the vagina may he obliterated by the development of a male type perineum and hence a vaginal orifice is not apparent.

    Virilization of the cloaca can also occur if the fetus is exposed to androgen in an androgenic drug ingested by the mother or, in many cases, the virilization is idiopathic. The end result in both of these circumstances is known as the intersex state. 

    At birth, investigation of the chromosomes, the endocrine status of the infant and ultrasound of the internal organs will lead to a rapid diagnosis, revealing whether the child is a female with a virilization state, which is most likely to be congenital adrenal hyperplasia , or a male who has been under-masculinized.

Brain Sex

    The sex of orientation of a human is influenced by many factors. Theories exist that this is genetically determined and it is most likely that our sexual orientation is in fact determined by our sexual make up. 

    However, this may be influenced by androgen exposure in utero or by other genetic and environmental factors that impact on this function . Enormous care has to be taken before a final decision is made un the sex of rearing of those individuals who are uncertain about their sexual orientation.

Puberty

    The hypothalamus pituitary-ovarian axis is function- ally complete during the latter half of fetal life. Follicle-stimulating hormone (FSH) levels are suppressed from 20 weeks' gestation by the production of estrogen by the placenta and by the fetus itself. At birth, the fetus is separated from its placenta and therefore the major source of estrogen is removed. 

    The FSH level then rises in response to the hypooestrogenic state of the fetus and remains elevated for some 6-18 months after birth. During this time it is suppressed due to the central inhibition of the production of gonadotrophin-releasing hormone (GnRH), which controls the pituitary production of FSH. 

    The mechanism by which this is achieved remains speculative, but almost certainly is controlled by a gene in the GnRH cell nucleus in the hypothalamus. It is possible that there is a relationship between the production of leptin, a peptide produced by fat cells, and the subsequent control of this gene.

    During childhood, FSH pulses are almost undetectable, and at around the age of 8 or 9 years a change gradually occurs in the function of the GnRH cell. This change begins with the production of single nocturnal spikes of GnRH and subsequently FSH. These spikes of FSH increase in frequency during the night-time hours over a period of 1-2 years. 

    Eventually, the frequency of the FSH pulses increases such that they are detectable in the daylight hours, and there- after, after a period of 4-5 years, a fully functional production of GnRH with normal adult frequency and pulse amplitude leads to the establishment of the ovulatory menstrual cycle. Puberty therefore occurs over a total of 5-10 years, and involves five types of development (see box below).