The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, Cooper Hospital/University Medical Center, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Camden, New Jersey, USA
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Abstract |
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Key words: oestrogen/ovarian failure/reversal
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Introduction |
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Pregnancies in women with hypergonadotrophism and oestrogen deficiency are much less common. Anecdotal reports of pregnancies despite apparent ovarian failure have appeared. Though some apparently occurred without any therapy (Alper et al., 1986; Shanis and Check, 1992
), most cases involved women who were on some form of oestrogen replacement (Polansky and DePapp, 1976
; Shangold et al., 1977
; Shapiro and Rubin, 1977
; Szlachter et al., 1979
; Ohsaiva et al., 1985
; Check et al., 1989a
, 1990c
). Some ovulations and pregnancies followed human menopausal gonadotrophin (HMG) therapy (Johnson and Peterson, 1979
; Tanaka et al., 1982
; Fleming et al., 1984
; Check, 1990a
). Some women failed to ovulate with HMG alone, but were successful when oestrogen and HMG were combined (Check and Chase, 1984
; Check et al., 1989b
, 1990c
, 1991
).
When counselling patients it is sometimes of benefit to know extreme limits. Women seeking help with infertility might be more willing to try a particular avenue of treatment, even if the odds of success are quite low, as long as a precedent exists. The purpose of this manuscript is to describe three cases that may represent the women with the highest documented concentrations of serum FSH (cases 1 and 2) and the oldest woman with ovarian failure (case 3) to have successful deliveries using their own gametes.
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Case report |
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Case 2
A 35 year old woman presented with primary infertility and oligomenorrhoea with intervals between menses of more than 2 months but less than 3 months. She was diagnosed previously at another reproductive endocrine practice with incipient ovarian failure based on an early follicular phase serum FSH of 22 mIU/ml while the serum oestradiol was <20 pg/ml. By history she was positive for anti-ovarian antibodies. She had also failed to achieve a rise in her serum oestradiol above 50 pg/ml despite two cycles of clomiphene citrate (50 mg x5 days and 100 mg x5 days) and two cycles of HMG therapy.
On her initial presentation, 36 days from her last menses, her FSH was 105 mIU/ml and LH was 89 mIU/ml. Menses were induced with medroxyprogesterone acetate (MPA) 10 mg and ethinyl oestradiol 0.02 mg. Her day 3 serum FSH was 69 mIU/ml while the serum oestradiol was 56 pg/ml. After 4 days of continued ethinyl oestradiol therapy (0.02 mg), the serum oestradiol increased to 671 pg/ml with an 18.3 mm dominant follicle. After follicle collapse she was treated with progesterone vaginal suppositories 100 mg twice daily plus oral oestradiol 2 mg. She failed to conceive. Her day 3 FSH for her next cycle was 127 mIU/ml and the serum oestradiol was 45 pg/ml. She was treated with 0.04 mg ethinyl oestradiol and by day 14 the serum oestradiol increased to 185 pg/ml and the FSH was down to 16 mIU/ml. She was given 75 IU of HMG for 2 days and the follicle increased to a 13.6 mm diameter and the serum oestradiol was 254 pg/ml. She was increased to 225 IU HMG for 1 day and given 10 000 units human chorionic gonadotrophin (HCG) the following evening (she was unable to return for blood or ultrasound tests on the day of HCG injection). The oocyte was released by day 19 and she was supplemented with progesterone vaginal suppositories 100 mg twice daily and oral oestradiol 2 mg. She conceived in this cycle and had a successful full-term delivery.
Case 3
A 45 year old woman with primary infertility of 5 years duration sought help. Her last menstrual period was 6 months previously. She had a serum FSH concentration drawn 3 months prior to her initial visit and it was 35 mIU/ml. Two attempts to induce menses with MPA 10 mg for 13 days failed to induce menses. Her serum oestradiol upon presentation was 15 pg/ml and her serum FSH was 43 mIU/ml. Her husband's semen analysis was considerably subnormal at a concentration of 3.3x106/ml with only 20% motility. They were not interested in IVF with intracytoplasmic sperm injection.
She was placed on ethinyl oestradiol 0.02 mg per day and she was monitored by serial serum FSH and oestradiol. The serum FSH gradually decreased to a concentration of 17 mIU/ml by day 18 with the serum oestradiol reaching 212 pg/ml, and on ultrasound a follicle with an average diameter of 18.3 mm was found. She was given 10 000 units of HCG and an intrauterine insemination (IUI) was performed 40 h later. She was given extra progesterone supplementation 100 mg x2/day of vaginal suppositories but she failed to conceive. During the luteal phase, the ethinyl oestradiol was stopped and 4 mg oral oestradiol was given. She failed to conceive and the progesterone and oral oestradiol were stopped and 0.02 mg of ethinyl oestradiol was given once again. On day 11 she attained a serum oestradiol of 236 pg/ml with a serum FSH of 11 pg/ml and had one dominant follicle measuring 19.2 mm. Following IUI, progesterone vaginal suppositories were again administered and she conceived during that cycle. She delivered a full-term healthy baby.
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Discussion |
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The three cases described here represent, we believe, in cases 1 and 2, women successfully conceiving with the highest serum FSH concentrations recorded to date, and in case 3 the oldest woman with apparent overt menopause to ovulate and have a normal pregnancy. The importance of reporting these cases is that if a patient with hypergonadotrophism requests fertility help and desires pregnancy with their own gametes, they should not be denied such treatment because of the belief that their high concentration of serum FSH precludes any chance of successful conception, or that their age (at least up to 45 years) makes pregnancy with their own gametes impossible. Instead they should be advised that although conception is highly unlikely, and that donor oocytes would be far more efficacious, nevertheless, at least two natural pregnancies were recorded with serum FSH concentrations >100 mIU/ml and another with very advanced age and apparent overt ovarian failure.
The authors have a second reason for wanting to present these cases besides the establishment of upper limits for concentration of serum FSH and age with elevated FSH for the achievement of successful pregnancies. There are no controlled studies that determine the mechanism for ovulation despite elevated FSH and oestrogen deficiency. Though most ovulations have occurred with women on oestrogen therapy, it is not clear if the ovulation could have occurred fortuitously independent of oestrogen.
However, the possibility exists that oestrogen treatment may increase the likelihood of ovulation despite hypergonadotropic hypogonadism. One hypothesis is that it may improve the sensitivity of the FSH receptor. Another hypothesis is that the woman's chronic FSH elevation leads to down-regulation of the FSH receptors in the few remaining follicles, leading to the inability to respond to either endogenous or exogenous FSH. However, by lowering the serum FSH, the FSH receptors are restored and the follicles can now once again respond to gonadotrophins.
The distinction between the two hypotheses of how oestrogen therapy may help to facilitate ovulation despite hypergonadotrophism is clinically important because if actual lowering of the elevated FSH concentrations is critical, then better results would be likely to occur if a pharmacological dosage of oestrogen is used rather than a physiological replacement dosage. There are some anecdotal published reports that support the importance of actually lowering the serum FSH. There is some evidence that lowering the serum FSH by the use of the gonadotrophin-releasing hormone agonist leuprolide acetate can improve the chances of ovulation without the use of exogenous oestrogen (Check et al., 1988, 1990b,Check et al., c
). Another case report suggested the same conclusions in a different manner by demonstrating that a woman who developed ovarian failure after taking follicle stimulating drugs to `strengthen' her ovulation was able to form multiple follicles and generate a serum oestradiol >800 pg/ml with her own endogenous gonadotrophins merely by stopping these drugs and allowing her FSH concentrations to decrease spontaneously (Check, 1992
).
Furthermore, the frequency of induced ovulations in a series of 100 consecutive patients with ovarian failure with a minimum of 1.5 years of amenorrhoea by using pharmacological dosages of ethinyl oestradiol in the majority and leuprolide acetate in a minority seemed to be too frequent and too consistent (especially with 19% achieving pregnancies) to be explained by mere spontaneous ovulation, as is sometimes seen in women on oestrogen replacement (Check et al., 1990c). Based on the relative paucity of published case reports of pregnancies resulting soon after oestrogen replacement, despite a high percentage of these patients being so treated, there appeared to be better success when higher dosages of oestrogen are used.
It is unlikely (because of the dearth of successful pregnancy cases) that a prospective study could be performed comparing efficacy of pharmacological dosages versus physiological replacement dosages of oestrogen for hypergonadotrophic hypogonadism. Even if such a study could be performed, and a pharmacological dosage of oestrogen proved no better then physiological replacement, there is an advantage of using ethinyl oestradiol as the type of oestrogen. In contrast to most other oestrogen preparations, ethinyl oestradiol does not falsely raise the serum oestradiol concentrations when performing most assays for serum oestradiol. Thus it allows for monitoring by simple blood analysis to determine if a follicle is recruited and to allow timing of intercourse, potential boosting of oocyte maturation by using exogenous gonadotrophins, and determining where to add luteal phase support with extra progesterone. Cases 1 and 3 achieved mature follicles with just ethinyl oestradiol and case 2 did not have a boost of gonadotrophins until maturation was significantly advanced (and it is not clear that the gonadotrophin boost was essential).
The relatively quick success of these patients with very inexpensive therapy allows the treating physician at least to advise a couple not interested in using donor oocytes or adoption that, although a successful outcome is unlikely, there does not appear to be a ceiling on the FSH concentration where conception in a woman with incipient ovarian failure is not possible. Furthermore, they can be advised that there is at least one precedent for temporary reversal of apparent overt menopause with successful delivery in women up to the age of 45 years.
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Notes |
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References |
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Submitted on January 12, 2000; accepted on May 4, 2000.