Hirsutism treatment with gonadotrophin releasing hormone analogs (GnRHa)

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Gonadotrophin Releasing Hormone Analogs for Hirsutism

Gonadotrophin releasing hormone analogs act as anti-androgens by suppressing its ovarian production. Hence, it is also a treatment for androgen-related disorders like hirsutism, hypertrichosis and their underlying ailments like Polycystic Ovary Syndrome (PCOS).

Gonadotrophin Releasing Hormone Analogs suppress gonadal hormone synthesis by imitating GnRH and attaching to target pituitary receptors with ‘high affinity’. The commonly used analogs are potent GnRH agonists (GnRHa). A long-term treatment with a GnRHa like leuprolide acetate acts against ovarian steroidogenesis by inhibiting pituitary LH and FSH production. This in turn reduces the concentration of circulating testosterone and androstenedione, but without affecting adrenal androgens.

Effectiveness of GnRHa

Research has proved that GnRH agonists result in substantial clinical recovery from hirsutism especially in patients with PCOS (ovarian hyperandrogenism). In PCOS patients, GnRHa treatment results in serum androgen concentration to drop to degrees similar to those in postmenopausal women within 1–2 months of administration. However, research about its effectiveness has come up with mixed results depending on the span of treatment for hirsutism.

One study was conducted on eight hirsute women. They were subcutaneously administered GnRHa in doses of 3.6 mg every month for a period of 1 year with simultaneous administration of transdermal estrogen and cyclic MPA starting on the third month of therapy. In these patients, there was noteworthy reduction in the F–G score of evaluating hirsutism, after 90 days of treatment. The survey also reported a constant progressive drop in the scores even after a 12-month gap in therapy.

Moreover, the benefits continued to last after 6 months of stopping the therapy, since the F–G count in these women had not returned to levels before treatment had started. Most of these women also reported uninterrupted progestin withdrawal bleeding, negligible menopausal manifestations and no serious drop in lumbar bone mineral density either.

This survey was placed side-by-side another that involved hirsute women treated with either GnRHa with hormone supplementation therapy or oral contraception. Here it was found that the former was better received and was more effective in treating hirsutism than the latter.

In another survey conducted by Azziz and others in 1995, it was concluded that treatment with leuprolide acetate and cyclic estrogen-progestin therapy showed speedier and better results in the treatment of hirsutism when contrasted with isolated OCP therapy. This evidence was supported by two other groups of researchers who also came up with the fact that GnRHa therapy proved better than OCP use.

However, a similar survey conducted by Carr and others reported no difference (at 3 and 6 months in objective counts of hair growth) in women undergoing GnRHa and OCP, isolated GnRHa, or isolated OCP therapy. However, they did report the highest and fastest blocking of serum androgens after 3 months in the survey group that was being administered GnRHa and OCP and lesser adverse effects than GnRH analogs alone.

Disadvantages of GnRHa

Though GnRHa have strong clinical potency in ensuring a hypogonadal state, they have a number of disadvantages and serious side effects.
They are:

  • GnRHa is expensive: Comparative studies have shown that a combination treatment of GnRH analog and OCP for hirsutism have the same results as a flutamide/OCP or cyproterone acetate and ethinyl estradiol treatment. But the GnRH analog has the disadvantage of being much more expensive.
  • GnRHa needs to be injected: Leuprolide [Lupron] in a dose of 3.75 mg of the depot formulation must be intramuscularly injected once a month. Alternatively an intranasal spray of Nafarelin [Synarel] in a dosage of 200 f-Lg to be used twice a day intranasally.
  • Long-term use of GnRHa has serious side effects. Hence experts advice that they should be prescribed to patients who fail to reap results from other forms of therapy with oral contraceptives and anti-androgens.

Some experts have also suggested that only severely hirsute and hyperinsulinemia patients be given GnRHa therapy. However, though use of oral contraceptive pills has been known to raise insulin resistance, it has been found that GnRHa treatment improved insulin sensitivity. Hence, it has been considered of added advantage to PCOS patients.

Also, the potent blocking of ovarian productions triggered by GnRHa results in simultaneous estrogen deficiency. This results in instant hypoestrogenic adverse effects like vasomotor instability (hot flashes), vaginal dryness, decreased breast size and mood swings. Additionally there is the dangerous deficiency of bone mineral density raging from as high as 4% after 6 months of treatment.

Antidotes to these side effects include using estrogen and progestin doses in the form of an oral contraceptive pill (OCP) or as hormonal replacement therapy. The addition of an OCP is suggested to prevent bone loss and the vasomotor symptoms related to hypoestrogenism, while still ensuring the benefits of speedy androgen decrease caused by GnRHa treatment.

Moreover, it has also been suggested that the continued use of OCP after stopping GnRHa therapy, may also plug the quick re-growth of hair in the case of hirsutism. However, a lot more research needs to be done for more conclusive evidence. Also, there are controversies regarding the estrogenic therapy effects. Many experts also suggest that in case of a ‘single-agent therapy’ GnRHa should ideally be administered for only 6 months.

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