Ovulation Induction and Controlled Ovarian Stimulation, 2st ed.

6. Management of Hypogonadotrophic-Hypogonadism

Roy Homburg1

(1)

Homerton Fertility Centre, Homerton University Hospital, London, UK

Abstract

Hypogonadotrophic-hypogonadism (hypothalamic-pituitary failure -WHO Group I), is a situation in which gonadotrophin concentrations are so low as to be completely unable to stimulate follicle development and oestrogen production from the ovaries. Anovulation, amenorrhea and hypo-oestrogenism are the consequences. There are several possible causes for this condition which may be hypothalamic or pituitary. Hypothalamic causes include: Weight-related amenorrhea, stress, strenuous exercise, Kallmann’s syndrome, craniopharyngioma, debilitating systemic diseases, idiopathic. Pituitary causes: Hypophysectomy, radiotherapy, Sheehan’s syndrome. If infertility is not a concern, every patient with hypogonadotrophic-hypogonadism over the age of menarche should be treated with hormone replacement therapy with cyclical oestrogen and progestins. For those desiring a pregnancy, if the pituitary is intact and the hypothalamus is failing to function, ‘replacement therapy’ with pulsatile GnRH is highly effective, if a little cumbersome. Direct stimulation of the ovaries with gonadotrophins serves the purpose for ovulation induction whether the cause is of hypothalamic or pituitary origin. If the cause of the amenorrhea is an extreme low body weight, every attempt should be made to increase weight before starting treatment.

Keywords

Hypogonadotrophic-hypogonadismGonadotrophinHypothalamic-pituitary failureOestrogenAnovulationAmenorrheaHypo-oestrogenismHypothalamicAnorexia nervosaStressStrenuous exerciseKallmann’s syndromeCraniopharyngioma debilitating systemic diseasesIdiopathicPituitaryHypophysectomyRadiotherapySheehan’s syndromeHaemorrhageProgestinsOsteoporosisGnRHGonadotrophin-Releasing HormoneNeuro-hormoneHypothalamusFSHLHGonadotrophinsLuteal phaseOHSSMonofolliculicular ovulationhCGGranulosa cells

Hypogonadotrophic-hypogonadism (hypothalamic-pituitary failure -WHO Group I), is a situation in which gonadotrophin concentrations are so low as to be completely unable to stimulate follicle development and oestrogen production from the ovaries. Anovulation, amenorrhea and hypo-oestrogenism are the consequences. There are several possible causes for this condition.

Hypothalamic Causes

·               Weight-related amenorrhea – loss of weight due to a crash diet or frank anorexia nervosa.

·               Stress.

·               Strenuous exercise – e.g. marathon running, ballet dancers.

·               Kallmann’s syndrome – hypothalamic amenorrhea associated with anosmia.

·               Other causes include craniopharyngioma, debilitating systemic diseases, idiopathic.

Pituitary Causes

·               Hypophysectomy.

·               Radiotherapy for pituitary tumours.

·               Following severe post-partum haemorrhage (Sheehan’s syndrome).

If infertility is not a concern, every patient with hypogonadotrophic-hypogonadism over the age of menarche should be treated with hormone replacement therapy with cyclical oestrogen and progestins. This serves the dual purpose of prevention of the consequences of oestrogen deficiency (e.g. osteoporosis and possibly cardio-vascular disease) and the preservation of uterine function with regard to future conception.

For those desiring a pregnancy, if the pituitary is intact and the hypothalamus is failing to function, ‘replacement therapy’ with pulsatile GnRH is highly effective. Direct stimulation of the ovaries with gonadotrophins also serves the purpose for ovulation induction whether the cause is of hypothalamic or pituitary origin.

If the cause of the amenorrhea is an extreme low body weight, every attempt should be made to increase weight before starting treatment. This will not only ease the treatment burden but is also very important for the successful outcome of an ensuing pregnancy.

6.1 Pulsatile Gonadotrophin-Releasing Hormone Therapy

Gonadotrophin-releasing hormone (GnRH) is a decapeptide, made up of ten amino acids. It is a neuro-hormone synthesized by nerve endings in the anterior hypothalamus which courses the very short journey (about 1 cm) from the anterior hypothalamus to the anterior pituitary in the portal vessels. There it releases FSH and LH.

Because of its very short half-life and the inability to measure its concentrations in the human peripheral circulation, the knowledge of the physiological action of gonadotrophin-releasing hormone has been learnt from charting the release of the gondotrophins, principally LH. It soon became apparent that GnRH is released in a pulsatile fashion and that the frequency and amplitude of the pulses can be changed by the influence of various factors on the hypothalamic pulse generator. In the follicular phase of a normal ovulatory cycle, pulses of LH, reflecting pulses of GnRH, are apparent about once an hour whereas in the luteal phase these are seen every 4 h. Pulses of FSH release are harder to detect as they are smaller and more infrequent. What has become apparent is that GnRH is a single hormone capable of releasing both LH and FSH from the pituitary gonadotrophs. The amount and timing of release of these hormones is critical for obtaining a normal ovulatory cycle and these are dependent not only on the amount, timing and pattern of pulsatile release of GnRH itself but also on the endocrine milieu of the anterior pituitary.

Once it was synthesized and made available for therapy, it became apparent that continuous infusion did not produce the desired release of gonadotrophins but, paradoxically, down-regulated their receptors and suppressed their release. When an agonist of GnRH was developed this had the same effect. This discovery proved to be extremely important and revolutionized reproductive physiology and eventually treatment. It also became apparent that pure, native GnRH, administered in a pulsatile fashion, could be utilized as excellent replacement therapy for hypothalamic-pituitary failure when the pituitary was intact.

When the cause of anovulation is hypothalamic failure, the classical replacement therapy is with pulsatile GnRH. This is administered through an infusion pump, very similar to an insulin pump apparatus, either subcutaneously or intravenously. The pump is set to give a bolus of 15–20 μg subcutaneously or 5–10 μg intravenously every 60–90 min. Some prefer the subcutaneous route as very occasional thrombophlebitis has been experienced at the site of the indwelling needle. With either mode of delivery, this is extremely effective treatment for the induction of ovulation for women who have idiopathic hypothalamic hypogonadotrophic-hypogonadism, Kallmann’s syndrome or weight-related amenorrhea, yielding pregnancy rates well in excess of 80 % [1]. Following ovulation, the pump must be either continued into the luteal phase or discontinued and luteal phase support given, until either pregnancy is established or menstruation ensues.

The advantages of this form of treatment are that almost no monitoring is required, OHSS does not occur and the very high rate of monofolliculicular ovulation ensures a multiple pregnancy rate of <5 %. Multiple pregnancies with this treatment are rare but most often occur in the first cycle of treatment or when hCG has been given to trigger ovulation [2]. The main disadvantages are the inconvenience of wearing the pump and accoutrements and consequently, limited patient acceptability as well as relatively high cost.

For women with hypothalamic-pituitary failure who have an intact pituitary gland, there is little doubt that results and safety dictate that I would prefer to treat their anovulation and infertility with pulsatile GnRH rather than exogenous gonadotrophin therapy. If this cumbersome treatment is accepted by the patient, the chances of obtaining a normal, singleton livebirth by treatment almost completely devoid of complications are extremely high. This form of treatment has, however, become almost extinct and treatment by direct stimulation of the ovaries with gonadotrophins has largely replaced it.

6.2 Gonadotrophin Therapy

Direct stimulation of the ovaries with gonadotrophins has the advantage in this condition that it is effective regardless of whether the cause of the hypogonadotrophic-hypogonadism is of hypothalamic or pituitary origin.

The gonadotrophin preparation used for the induction of ovulation in this condition must contain either LH or hCG to induce LH activity, in addition to FSH [3]. The use of FSH alone may well produce follicular development but no oestrogen production will ensue and this severely limits the chances of a successful ovulation and does not allow the development of a receptive endometrium. The ‘two gonadotrophin, two cell hypothesis’ dictates that LH activity is needed to produce androgens from theca cells which serve as the substrate for oestrogen production (see Chap. 2). As women with hypogadotrophic-hypogonadism do not discharge LH, no androgen substrate is available and hence, no oestrogen production is possible.

The ovaries of women with hypogonadotrophic-hypogonadism lack exposure to endogenous gonadotrophins and this probably limits the number of FSH receptors present in granulosa cells. This is the reason why the response to exogenous gonadotrophin therapy may often be slow, insinuating that a period of priming is involved during the first treatment cycle. Patience and a titration of the appropriate gonadotrophin dose is therefore required for optimal ovulation induction.

Due to the lack of endogenous LH activity in these women, a dose of 10,000 units of urinary hCG (500 mcg of recombinant hCG) should be used for ovulation triggering and this should be backed up with vaginal micronized progesterone suppositories to support the luteal phase.

In summary, ovulation induction for the treatment of infertility due to hypogonadotrophic-hypogonadism has an excellent prognosis and pregnancy rates in excess of 80 % may be expected.

References

1.

Homburg R, Eshel A, Armar NA, et al. One hundred pregnancies after treatment with pulsatile luteinising hormone releasing hormone to induce ovulation. Br Med J. 1989;298:809–12.CrossRef

2.

Braat DD, Schoemaker R, Schoemaker J. Life table analysis of fecundity of intravenously gonadotrophin-releasing hormone treated patients with normogonadotropic and hypogonadotropic amenorrhea. Fertil Steril. 1991;55:266–71.PubMed

3.

The European Recombinant Human LH Study Group. Recombinant human luteinizing hormone (LH) to support human follicle-stimulating hormone (FSH)-induced follicular development in LH and FSH deficient anovulatory women: a dose-finding study. J Clin Endocrinol Metab. 1998;83:1507–14.