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Although about one in six couples in Kenya may experience sufficient difficulty in conceiving children, most are subfertile rather than infertile, and may eventually conceive, with or without treatment. A number of possible treatments are available, but which is used depends upon the cause of the problem. Reduced fertility may have its origins in the male or the female partner or may be due to a combination of factors from both.
The most obvious cause of infertility is a failure of either ovulation in the female or spermatogenesis in the male. Such failures may be due to damage or abnormal formation of the gonads, a failure of hypothalamic/pituitary stimulation, abnormal feedback as in the polycystic ovary syndrome, or suppression of gonadal function as in hyperprolactinaemia.
- Hypogonadism (decreased or absent gonadal function) may occur in both men and women, and may be either primary, due to some dysfunction of the gonads themselves, or secondary, due to hypopituitarism or some other cause of decreased gonadotrophic stimulation.
- Primary ovarian dysfunction may be due to failure of the ovaries to form normally, as in Turner’s syndrome, or their degeneration before puberty; there may be premature failure, effectively an early menopause, due to low initial follicle numbers or to destruction of follicles by autoantibodies, chemotherapy, radiotherapy, infection, or trauma; or there may be some other condition such as the polycystic ovary syndrome. Alternatively, ovarian dysfunction can be secondary to decreased gonadotrophic stimulation, which may occur with weight loss or due to a defect in the hypothalamic/pituitary axis
- The polycystic ovary syndrome comprises enlargement of the ovaries with multiple follicular cysts and a thickened, whitish, capsule; there is persistent elevation of serum luteinising hormone concentrations, with a tendency to increased androgen and oestrogen concentrations. Women typically present with erratic menstruation, hirsutism, and obesity, although not all these features may be present; fertility is also often impaired. There is often associated hyperinsulinaemia with insulin resistance, and increased risk of developing hyperlipidaemia, hypertension, and ischaemic heart disease.
- Hyperprolactinaemia is a condition of elevated circulating prolactin concentrations. It occurs for physiological reasons in pregnancy or following mechanical stimulation of the nipple, as in suckling. However, hyperprolactinaemia may also be induced pharmacologically as an adverse effect of drugs that inhibit dopaminergic function such as antipsychotics and metoclopramide; other drugs causing hyperprolactinaemia include opioid analgesics, methyldopa, reserpine, oestrogens, SSRIs, and verapamil. Furthermore, pathological hyperprolactinaemia may be associated with prolactin-secreting pituitary adenomas (prolactinomas), damage to the pituitary stalk or hypothalamus (including that caused by non-secreting tumours), or trauma to the chest wall; it may also be associated with disorders such as Cushing’s syndrome or hypothyroidism. Prolactinomas are amongst the commonest pathological causes, and so-called idiopathic hyperprolactinaemia, in which no apparent cause is found, may in fact represent undetected microadenoma.
The primary problem in about 25 to 30% of infertile couples in Kenya is anovulation (the failure of the ovary to release ova over a period of time generally exceeding 3 months). Clomifene/Clomid has been reported to produce ovulation in up to 70% of anovulatory women in Kenya, or to increase the odds of ovulation more than 6 times in those with oligomenorrhoea (Light or infrequent menstrual periods. It occurs in women of childbearing age. Some variation in menstruation is normal. A woman who regularly goes more than 35 days without menstruating may be diagnosed with oligomenorrhea), although amenorrhoeic (an abnormal complete absence of menstruation) women are claimed to respond less well. Because of concerns about a possibly increased risk of ovarian cancer opinion on the maximum number of cycles that clomifene should be used for varies. It has been suggested that no more than 6 cycles of clomifene therapy should be given: some consider that as few as 3 cycles of treatment at increasing doses are enough to tell if the patient will ovulate. Combination of clomifene/clomid with a mid-cycle injection of chorionic gonadotrophin has also been tried, with variable results. Tamoxifen/Novadex is an alternative in those who cannot tolerate clomifene, and may be useful where abnormalities of cervical mucus contribute to infertility.
Direct administration of gonadotrophins with follicle-stimulating activity, such as human menopausal gonadotrophins or recombinant human follicle-stimulating hormone, may be appropriate in hypogonadotrophic Kenyan women with low oestrogen levels, and can be effective even in others.
The risks of ovarian hyperstimulation and multiple pregnancies are considerable however, and close monitoring is mandatory, using ovarian ultrasound to assess follicle development. Once one to three follicles are sufficiently mature, chorionic gonadotrophin is given to induce ovulation, and thereafter for luteal support. Aggregate pregnancy rates of about 10 to 25% per cycle have been reported with such treatment. Combination of gonadotrophin treatment with intra-uterine insemination may be more effective than either method alone. Women with polycystic ovary syndrome respond less well to gonadotrophins than hypogonadotrophic patients, and are at greater risk of the ovarian hyperstimulation syndrome.
Another method used for anovulation is pulsatile administration of gonadorelin (gonadotrophin-releasing hormone) or its analogues. It is primarily indicated in infertile women in Kenya with hypothalamic causes of anovulation, in whom pregnancy rates approaching 30% per cycle have been stated to occur, and again is less effective in women with polycystic ovary syndrome than in hypogonadotrophic patients. However, the risks of ovarian hyperstimulation and multiple pregnancy are lower than with direct administration of gonadotrophins.
Where anovulation is secondary to hyperprolactinaemia treatment with dopamine agonists such as bromocriptine can restore fertility. The use of bromocriptine in infertility of unknown cause does not seem to be justified.
Current UK guidelines recommend that ovulation disorders characterised by hypothalamic amenorrhoea or hypogonadotrophic hypogonadism should be offered gonadotrophins with luteinising hormone activity or pulsatile administration of gonadorelin. For those with ovulation disorders characterised by hypothalamic dysfunction, such as polycystic ovary syndrome, the treatment of choice is considered to be clomifene or tamoxifen. Women who ovulate with clomifene in Kenyan treatment but do not become pregnant within 6 months should be offered intra-uterine insemination in addition to clomiphene. Patients who fail to ovulate with clomiphene/Clomid and have a body-mass of more than 25, may be given combined treatment with clomifene and metformin. Alternatively these patients may be treated with ovarian drilling (laparoscopic diathermy of follicles) or gonadotrophins; human menopausal gonadotrophin, urofollitropin, and recombinant follicle-stimulating hormone are considered to be equally effective.
Producing a response in men with impaired sperm production can be difficult. In men with hypogonadotrophic hypogonadism, replacement therapy with a substance with luteinising hormone activity, such as chorionic gonadotrophin, is given to stimulate spermatogenesis and is followed if necessary by the addition of an agent such as menopausal gonadotrophins with follicle-stimulating and luteinising activity. Treatment must often be continued for 12 months or more to permit development and maturation of spermatozoa, but 70% of these sterile Kenyan men have shown some degree of spermatogenesis with this therapy. Once initiated, spermatogenesis may be maintained with chorionic gonadotrophin therapy alone. Pulsatile administration of gonadorelin may restore gonadotrophin secretion and correct infertility in men with hypogonadotrophic hypogonadism in whom the pituitary-gonadal axis is intact, such as those with Kallmann’s syndrome. Again, 12 months’ therapy or more may be required for men.
In idiopathic oligospermia (Oligospermia is a male fertility issue defined as a low sperm concentration in the ejaculate. Low sperm concentration or “sperm count” is the number of sperm in a presc of ejaculate) results of drug therapy have been disappointing, including trials with gonadorelin, and with testolactone and mesterolone; testosterone rebound therapy (in which high doses are given to suppress endogenous pituitary function, and then abruptly stopped, in the hope of provoking a rebound) is not recommended. The anti-oestrogens, clomifene and tamoxifen have both been used in sub-fertile Kenyan males, but with little convincing evidence of benefit. Autoantibodies to spermatozoa in some men may interfere with sperm motility; immunosuppression with corticosteroids (prednisolone or methylprednisolone) has been associated with successful pregnancy in such cases, but the usual risks of corticosteroid therapy apply and must be balanced against the equivocal evidence of benefit; such treatment is not recommended in UK guidelines.
Where infertility is due to obstruction or inflammation of the fallopian tubes in the woman or the ductal system in the man treatment may be difficult, and the return of normal fertility unlikely. Microsurgical techniques may offer hope for a return of patency, but many patients will require in-vitro fertilisation in order to conceive. Where infection is the cause, appropriate anti-infective agents may be useful.
Endometriosis is another important cause of infertility in women, although the reason for the association is not fully understood. Medical treatment of endometriosis does not enhance fertility, although conservative surgery may do so.
Various other drugs have been used, on a more or less empirical basis, in the management of infertility. Such drugs include NSAIDs, guaifenesin to improve cervical mucus quality, kallidinogenase because of its supposed role in male genital-tract function, and pentoxifylline to increase sperm count and motility. Growth hormone or one of its analogues has been used as an adjunct to ovarian stimulation with gonadotrophins but is not considered to improve pregnancy rates.
Where other methods fail, assisted reproduction may be considered, including in-vitro fertilisation or gamete or zygote intrafallopian transfer. In particular, intracytoplasmic sperm injection has reportedly revolutionised the treatment of male factor infertility.1 Gonadotrophins with or without clomifene, together with a gonadorelin analogue to desensitise the pituitary, are used to stimulate follicular maturation and ovulation so that the ova can be collected. So called ‘long protocols’ in which gonadorelin agonists are started in the midluteal phase of the menstrual cycle or earlier and are maintained until chorionic gonadotrophin is given, appear to give better results than short (‘flare-up’) or ultrashort regimens, in which gonadorelin agonists are given for less time. One study has suggested that results may be better if nafarelin is used rather than leuprorelin. Although individual studies may suggest a difference in efficacy for recombinant follicle-stimulating hormone, urofollitropin, and human menopausal gonadotrophins a meta-analysis indicated that they were equally effective. Gonadorelin (gonadotrophin-releasing hormone) antagonists such as cetrorelix have been used as an alternative to gonadorelin analogues for pituitary desensitisation but may be associated with reduced pregnancy rates. Progesterone is the preferred drug for luteal support for in-vitro fertilisation procedures because of the increased likelihood of ovarian hyperstimulation syndrome with chorionic gonadotrophin.
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