8.06 Fertility, sexuality

excitement: erection and vasocongestion of penis or clitoris, mucus secretion, heightened sexual awareness, skin flushing due to vasodilation,
plateau: intensification of these responses, increased heart rate, blood pressure, respiratory rate and muscle tension,
orgasmic: ejaculation in the male and rhythmic pelvic muscle contraction in the female,
resolution: subsidence of vasocongestion and systemic manifestations followed by relaxation to return the genitalia and body systems to their prearoused state

-ejaculation in males during which semen fills the urethra (emission) and is then expelled

-the refractory period. Females can respond to continued erotic stimulation following an orgasm and have further orgasms

Parasympathetic

-sympathetically induced contraction of the smooth muscle in the prostate, reproductive ducts and seminal vesicles
-emission of sperm and secretions (semen) into the urethra
-rhythmic contractions of skeletal muscles at the base of the penis which expel semen out of the urethra

The average volume of ejaculate is 3ml and contains 300-400 million sperm (120 million/ml)

On the basis of the number of sperm (should be above 20 million/ml) and their motility and structure

-stimulation of clitoris and surrounding structures leads to erection of clitoris via spinal reflex
-vasodilation of vulval and vaginal arterioles via parasympathetics
-vasocongestion of vaginal capillaries forces a transudate into the vaginal lumen (this acts as a lubricant together with mucus secreted by the vestibular glands at the vaginal orifice)
-during the plateau phase the uterus tilts forward which lifts the cervix and enlarges the upper two-thirds of the vagina, thus creating a space for ejaculate deposition
-during orgasm, rhythmic contractions of the pelvic skeletal muscles occur

Embryonic, neonatal, pubertal

hCG. It's long acting

LH (secreted from pituitary gonadotrophs with the LH subsequently travelling via the peripheral bloodstream to the testis)
It acts on highly specific G-protein coupled receptors located on the Leydig cell plasma membrane and linked to adenylyl cyclase

-It is exerted largely on the hypothalamus via neurons with androgen and oestrogen receptors
-Also exerted at the pituitary level mainly through local aromatisation of testosterone to estradiol

Largely bound to serum proteins
-tight, specific binding to sex-hormone binding globulin
-looser binging to albumin
-a small fraction is non-protein bound (free fraction)

By both:
-passive diffusion as a lipophilic molecule via plasma membranes
-protein-bound mechanisms

Binds to intracellular androgen receptor --> it converts the receptor to an activated, hinged, dimeric form, and the receptor sheds chaperone molecules (HSP70, HSP90 & others which would maintain receptor inactivity) --> The activated complex binds to DNA and acts as a ligand-activated transcription factor

By conversion to its two major bioactive metabolites, dihydrotestosterone (DHT) and estradiol (E2) which amplify or diversity, respectively, testosterone action.

Androgen insensitivity from a completely female to a virtually normal mildly undermasculinised male phenotype

It is converted in some tissues (prostate, skin) to DHT via 5-alpha reductase. This amplifies androgenic action because DHT is a more potent androgen than testosterone

It is under negative feedback from inhibin B secreted from mature Sertoli cells into the bloodstream

It has specific, high affinity G-protein linked receptors exclusively on Sertoli cells which are the key organisers of spermatogenesis.

Sertoli cells support, nourish and co-ordinate germ cells development through intimate cell-surface contact by tight junctions as well as through secreting and absorbing fluid, ions, metabolites and proteins; forming the blood-testis barrier and elaborate a distinctive adluminal compartmental fluid environment.

Mitosis, meiosis and spermiogenesis

Diploid precursor spermatogonia enter meiosis and traverse the blood-testis barrier --> spermatocytes undergo two stages of meiosis to become haploid round spermatids --> these amorphous cells metamorphose into a highly differentiated spermatozoa within the most central (luminal) layers of the epithelium --> immature spermatozoa are shed into the tubular lumen transported to the rete testis and epididymis --> they finally mature during epididymal transit and are stored in the cauda epididymis awaiting ejaculation takes place.

Klinefelter’s syndrome (47 XXY & variants), and various mutations involving the Y chromosome or autosomes
Androgen receptors are located on the X chromosome (hemizygous in men) and susceptible to many mutations which, in the absence of a second allele, are usually expressed clinically
Other disorders of sexual development leading to intersex conditions include disorders of testis development (mutations of SRY gene the testis determining gene and other related genes WT1, SF1, SOX9, DAX1, DHH, ATRX, ARX; DMRT, SOX8) and of Leydig cell androgen biosynthesis due to LH receptor or steroidogenic enzymes defects.

Absent or incomplete pubertal development and virilisation and infertility
- A genetic failure produce GnRH e.g. Kallmann's syndrome
- Severe weight loss or fever causing hypothalamic dysfunction and lack of GnRH secretion
- Drugs such as anabolic steroids or opiates which suppress GnRH release
- Tumours destroying GnRH neurones

A mutation on the KAL gene results in failure of migration of GnRH neurones from the olfactory placode to the hypothalamus in foetal life (together with failure of development of the olfactory nerve leading to anosmia

Loss of male secondary sexual characteristics (e.g. male pattern body hair, musculature), loss of libido and infertility
- Pituitary tumours
Pituitary infiltrates (iron deposition in hereditary haemochromotosis)

The germinal epithelium of the testis [the site of sperm production and thus fertility] is much more susceptible to damage than the Leydig cells so that most men with infertility have normal androgenisation and so may be unaware of their infertility until a semen sample is analysed

- Damage to the germinal epithelium e.g. mumps in adulthood causing testicular inflammation
- Y chromosome abnormalities affecting normal testicular development
- Severe direct testicular trauma
- Drugs e.g. cytotoxics
- Testicular irradiation

2 months

Volume: ≥ 2.0ml
Concentration: ≥ 20 million spermatozoa per ml
Motility: ≥ 50% with forward progression or ≥ 25% with rapid forward progression
Morphology: ≥ 15% normal forms
Vitality: ≥ 75% alive
pH: 7.2 – 8.0

The chance of getting pregnant

If a couple has not become pregnant in a year or two (suggesting a fecundability of <5%)

common condition in which tissue like the mucosa of the uterus (the endometrium) grows outside the uterus, poisoning a number of events important to conception and to normal implantation of the embryo; treatment can be medical, surgical or with assisted conception ; infertility is usually relative rather than complete

Measure the circulating concentration of progesterone on Day 21
Other methods:
- Serial ultrasound assessment
- Serial urinary LH estimation (to detect the mid-cycle LH surge that triggers ovulation)
- Mucus, temperature

T

A progestogen challenge test where oral progestogen is given for five days. If vaginal bleeding occurs withing a few days of stopping progesterone, (+ve gentogen test) the endometrium is well-oestrogenised and anovulation is probaby the cause of amenorrhoea
When the test is -ve, this suggests a hypothalamo-pituitary cause for amenorrhoea (such as hyperprolactinaemia) or, if the circulating concentration of follicle-stimulating hormone (FSH) is elevated (> 20 IU/L), irreversible ovarian failure

- An elevated concentration of luteinising hormone (> 10IU/L)
- Evidence of increased androgen secretion (slight elevation in testosterone and a reduced sex-hormone binding globulin concentration)
- Characteristic ultrasound appearances

Hysterosalpingography is useful for diagnosing tubal patency but gives only limited information about other aspects of pelvic pathology such as the presence of adhesions or endometriosis

Investigation for the presence of genital pathogens such as chlamydia trachomatis

Endometriosis, if present in large amounts, undoubtedly contributes to infertility by distorting pelvic anatomy but recent evidence suggests that the significance of mild endometriosis is limited.

Fibroids (benign leiomyomata) may be evident on pelvic ultrasound or at time of laparoscopy but in most cases are not significant in preventing conception.