Peter Kovacs, MD, PhD

Disclosures

February 28, 2005

Question

I have a patient para 1 who delivered 18 years ago and had severe postpartum hemorrhage. Later on, she developed amenorrhea. Her hormone profile revealed follicle-stimulating hormone (FSH) 3.2 IU/mL and luteinizing hormone (LH) 2 IU/mL. No withdrawal bleeding occurred after progesterone challange. She was finally diagnosed with Sheehan's syndrome. I tried ovulation induction with the menotropins preparation Humegon , but after 14 injections in 14 days she did not respond. What is the cause of the lack of response?

Iftikhar Sadique, FCPS (Ob/Gyn)

Response from Peter Kovacs, MD, PhD

Regular ovulatory ovarian function requires an intact hypothalamic-pituitary-ovarian axis. Disorder at any level may result in oligoanovulation. Gonadotropin-releasing hormone (GnRH) neurons in the mediobasal hypothalamus secrete GnRH in a pulsatile fashion. GnRH reaches the pituitary via the portal vessels and stimulates the release of FSH and LH. These gonadotropins will then maintain follicle growth and steroid production in the ovaries.

If the pituitary is injured, the production of 1 or several of the trophic hormones may become compromised. During pregnancy, the pituitary undergoes hypertrophy and becomes increasingly sensitive to ischemia. Ischemic necrosis of the pituitary may occur if the delivery is accompanied by significant blood loss and volume is not replaced adequately. Following such an event, women are typically unable to lactate. In addition, they may experience increasing fatigue, hair loss, and may develop amenorrhea. Symptoms and their severity depend on the extent of damage and the trophic hormones that are affected. Insufficient production of FSH, LH, prolactin, thyrotropin, or adrenocorticotropic hormone has various clinical presentations.

Sheehan's syndrome develops after ischemic injury to the pituitary. When one suspects pituitary insufficiency, it is important to assess the entire function of the pituitary. Provocative hormonal studies and imaging studies can provide the necessary information. When reduced production of any of the anterior pituitary hormones is observed, adequate replacement is important.

When gonadotropins are not produced in sufficient quantity, it is important to replace both FSH and LH. Although clomiphene citrate may work in some cases (when the destruction is only partial), it is more likely that injectable gonadotropins (human menopausal gonadotropin or the combination of recombinant FSH and LH) will be required. Stimulation should be initiated with a low dose, as the goal is to restore monofollicular development. Stimulation typically takes longer than in regularly cycling women. In a hypoestrogenic environment, it requires more time for the follicles to respond to stimulation. It is important to remain patient. If the dose is increased prematurely, one could end up with multifollicular growth, and the cycle may need to be canceled for that reason. Ultrasound and serum estradiol measurements can be used to monitor response. When a change in follicular size is not observed, a rising estradiol level may signal the onset of follicular development. If after 7-10 days of stimulation neither the ultrasound picture nor the hormone measurement indicates ovarian activity, the dose may be increased by a half or 1 ampule and maintained at that dose for another 7-10 days, if necessary. Repeat cycles (if needed) should get easier, as the ovaries have already been exposed to an estrogenic environment. Some suggest that pretreatment with estrogen-progestin will improve treatment outcome.

It is also important to support the luteal phase of these cycles. To maintain the function of the corpus luteum, either human chorionic gonadotropin may be administered or progesterone and estrogen both should be given. If repetitive ovulatory cycles are unsuccessful, intrauterine insemination or even in vitro fertilization may become necessary.

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