Galactorrhea and pituitary tumors in postpill and non-postpill secondary amenorrhea.

One hundred sixty-seven women with secondary amenorrhea were observed from six months to four years. In 66 patients, the amenorrhea followed the discontinuation of oral contraceptives (postpill) while in the remaining 101 the amenorrhea was not temporally pill related (non-postpill). Galactorrhea was present in 43 (65%) of those with postpill amenorrhea and in 32 (32%) of those with non-postpill amenorrhea (p less than 0.001). Tomography of the sella turcica was performed in the 75 women with galactorrhea and in the 35 without galactorrhea who did not have withdrawal uterine bleeding following progesterone administration and who had low or normal serum follicle-stimulating hormone levels (hypothalamic-pituitary failure). Forty of the 75 patients with amenorrhea and galactorrhea had radiographic evidence of a pituitary tumor whereas only eight of 35 patients with hypothalamic-pituitary failure without galactorrhea had an abnormal sella turcica (p less than 0.01). The incidence of radiographic abnormalities in those with galactorrhea was similar in both the postpill and non-postpill groups.     

Prolonged amenorrhea and oral contraceptives.

Of 106 consecutive women referred for secondary amenorrhea of more than 1 year's duration, 65 were diagnosed as having functional amenorrhea. Of these 65, 29 had amenorrhea directly following discontinuation of oral contraceptives (OC group) and 36 had never used oral contraceptives (NOC group). There was no difference in the incidence of prior menstrual irregularity in either group. Similarly, there was no difference in the resting serum estrone, estradiol, luteinizing hormone, follicle-stimulating hormone, and prolactin levels between the OC and NOC groups. Nor was there a difference between the OC and NOC groups in response to medroxyprogesterone acetate, clomiphene citrate, or luteinizing hormone-releasing factor. Of 106 patients, 17 were proven to have prolactinomas. Eight patients had a prior history of OC use, whereas nine did not. With the exception of elevated serum prolactin levels, there were no significant differences in biochemical tests or history of oral contraceptive use between the prolactinoma group and patients with prolonged "functional" amenorrhea (OC plus NOC groups). The lack of historical or biochemical difference between the OC and NOC subjects indicates homogeneity between groups, and does not support the existence of a "postpill" syndrome.     

Hyperandrogenemia as a cause of amenorrhea

The so-called postpill amenorrhea remains a much debated subject in gynecological endocrinology. We have therefore scrutinized the reproductive history and endocrinological parameters of 145 patients with the presumptive diagnosis of postpill amenorrhea, seen at our department during the last two years. 166 cases of secondary amenorrhea served as a control group. Both groups showed a high incidence of late menarche (20%), previous oligomenorrhea and elevated androgen serum levels. There were no significant differences between both collectives. These findings suggest that although oral contraceptives may unfavorably influence the menstrual cycle, there is no causal relationship between such agents and the development of secondary amenorrhea. It seems that in many cases of presumptive postpill amenorrhea the common juvenile hyperandrogenemic ovarian insufficiency might be the underlying problem.     

Amenorrhea with low normal thyroid function and thyroxine treatment

The effect of thyroxine treatment in cases of functional amenorrhea accompanied by low normally thyroid function was studied. During six months of follow-up, regular or single menstrual cycles were restored in ten of the 17 patients with thyroxine treatment and in four of the 11 patients without thyroxine treatment. During thyroxine treatment, thyroxine and free thyroxine index levels were elevated and serum testosterone levels decreased, but no significant changes were observed in serum estradiol, prolactin, follicle-stimulating hormone or luteinizing hormone levels. In the thyroid-releasing hormone/luteinizing-releasing hormone test, the thyroid-stimulating hormone response was markedly suppressed, but there were no changes in follicle-stimulating hormone, luteinizing hormone or prolactin responses. In one patient with primary hypothyroidism, regular menstrual cycles were restored and serum prolactin and thyroid-stimulating hormone levels normalized during thyroxine treatment. Thyroxine treatment seems to have benefits in some amenorrheic patients with low normal thyroid function.     

Altered androstenedione and estrone dynamics associated with abnormal hormonal profiles in amenorrheic subjects with weight loss or obesity

The present study was designed for exploration of hormonal disturbances underlying common forms of amenorrhea. Polycystic ovary syndrome (PCO) patients and obese amenorrheic subjects had significantly elevated estrone (E1) levels, elevated luteinizing hormone/follicle-stimulating hormone ratios, and an exaggerated luteinizing hormone response to luteinizing hormone-releasing hormone. However, androstenedione (delta 4A), the precursor of E1, was elevated only in PCO. Thus, the E1/delta 4A ratio, which provides an indirect index of aromatase activity in extraglandular sites, was raised in obese subjects as a group but not in PCO subjects. These findings suggest that elevated E1 levels, which give rise to abnormal gonadotropin secretion, arise from increased available androgens in PCO but from an increased effect of aromatase (present in adipose tissue) in obese subjects. Measurement of androgens and the E1/delta 4A ratio provides insights into the relative contributions of hyperandrogenemia and enhanced aromatase activity to the genesis of amenorrhea in these groups. In patients with suppressed estradiol levels associated with hyperprolactinemia or weight loss, follicle-stimulating hormone levels were suppressed, while luteinizing hormone was not elevated. Prolactin excess explains these findings in hyperprolactinemia. Plasma E1 levels and the E1/delta 4A ratio were suppressed in patients with weight loss, possibly as a consequence of reduced adiposity. This finding suggests that hypothesis that a minimum level of E1, dependent upon adequate adiposity, is critical for the normal mature function of the hypothalamic-pituitary-ovarian axis. Abnormal E1/delta 4A ratios, high in obesity-associated amenorrhea and suppressed in weight loss-associated amenorrhea, may provide specific markers for these groups of patients.     

Effects of lactation on hormonal levels in rural women

Luteinizing hormone, follicle-stimulating hormone and prolactin levels were compared in ten rural and ten urban women, all of whom were experiencing lactational amenorrhea. The values of luteinizing hormone and follicle-stimulating hormone were similar in both groups. The prolactin levels were significantly elevated in the rural group.     

Exaggerated gonadotropin response to luteinizing hormone-releasing hormone in amenorrheic runners

Most studies of exercise-induced amenorrhea have compared amenorrheic athletes (usually runners) with sedentary control subjects. Such comparisons will identify hormonal changes that develop as a result of exercise training but cannot determine which of these changes play a role in causing amenorrhea. To obviate this problem, we assessed reproductive hormone status in a group of five amenorrheic runners and compared them to a group of six eumenorrheic runners matched for body fatness, training intensity, and exercise performance. Compared to the eumenorrheic runners, the amenorrheic runners had lower serum estradiol concentrations, similar basal serum luteinizing hormone and follicle-stimulating hormone concentrations, and exaggerated responses of serum gonadotropins after administration of luteinizing hormone-releasing hormone (100 micrograms intravenous bolus). Serum prolactin levels, both basally and after thyrotropin-releasing hormone administration (500 micrograms intravenous bolus) or treadmill exercise, was similar in the two groups, as were serum thyroid function tests (including thyrotropin response to thyrotropin-releasing hormone). Changes in serum cortisol levels after short-term treadmill exercise were similar in both groups, and serum testosterone levels increased after exercise only in the eumenorrheic group. In neither group did such exercise change serum luteinizing hormone, follicle-stimulating hormone, or thyrotropin levels. We concluded that exercise-induced amenorrhea is not solely related to the development of increased prolactin output after exercise training. The exaggerated gonadotropin response to luteinizing hormone-releasing hormone seen in amenorrheic runners in comparison with matched eumenorrheic runners is consistent with a hypothalamic etiology for the menstrual dysfunction, analogous to that previously described in "stress-induced" or "psychogenic" amenorrhea.     

Amenorrhea: observations based on the analysis of luteinizing hormone-releasing hormone testing.

The basal serum gonadotropins--luteinizing hormone (LH) and follicle-stimulating hormone (FSH)--usually provide clues to the diagnosis of amenorrhea. This report analyzes the results of LHRH-testing (LH-releasing hormone) of a group of amenorrheic women at Duke University Medical Center between 1973 and '76. 130 patients with symptomatic amenorrhea underwent diagnostic testing with LHRH; extensive basal and dynamic laboratory tests and appropriate radiologic and operative studies were also performed. A control of 18 normally ovulatory women (18-35 years old) were tested during the early follicular phase of the menstrual cycle. The patients were grouped according to 13 diagnostic criteria for amenorrhea. Logarithms of 4 baseline and 13 response measurements were used to compare test results of both study and control groups. Gonadotropin measurements revealed a logarithmic distribution; each diagnostic category showed multiple significant differences when compared with the controls. The occurrence of significant changes in either positive or negative directions for both LH and FSH were the same in all the categories in the following response parameters: peak, mean change, area, and peak change, with exceptions for the FSH area and FSH peak in the postpill amenorrhea category. The findings in this study precludes the routine use of LHRH test as a differential diagnostic tool; rather its diagnostic use should be confined to pathophysiologic research.     

Celiac disease as a rare cause of primary amenorrhea: a case report

BACKGROUND: Primary amenorrhea can be due to abnormal functioning of the hypothalamic-pituitary axis or malformation of müllerian structures. Malnutrition due to chronic malabsorption can alter the axis and can be a cause of primary amenorrhea. CASE: A 20-year-old woman presented to us with primary amenorrhea and failure of development of secondary sexual characteristics. She had significant weight loss in spite of normal intake of diet. On investigation, she had microcytic hypochromic anemia, and her follicle-stimulating hormone and luteinizing hormone levels were low, while the thyroid-stimulating hormone and prolactin levels were normal. Her duodenal biopsy showed villus atrophy, and IgA antiendomysial antibody was positive, suggestive of celiac disease. The patient's condition improved markedly and attained menarche after 6 months of a gluten-free diet. CONCLUSION: Celiac disease should be considered in patients presenting with malnutrition and primary amenorrhea.     

Progress and therapy of stress amenorrhea.

Thirty-two patients with stress amenorrhea of less than 1 years duration were found to have withdrawal bleeding after progestin administration, normal serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and good responsiveness to LH-releasing hormone (LH-RH); ovulation was induced following the admininstration of clomiphene citrate. On the other hand, in 11 of 14 patients with stress amenorrhea of longer than 1 years duration, no bleeding followed the administration of progestin, and there were noted high serum FSH and LH levels, exaggerated release responsiveness to LH-RH, and atrophic vaginal smears and endometrium. In addition, it was difficult to induce ovulation by various treatments. The findings suggest that dysfunction in the hypothalamic cyclic (not tonic) center regulating ovulation was the originating factor in the amenorrhea in question and that ovulation should be induced at least once yearly to prevent ovarian function from declining in this type of anovulatory state existing for more than 1 year.     

Successful pregnancy following low-dose hCG administration in addition to hMG in a patient with hypothalamic amenorrhea due to weight loss

We describe successful ovulation induction with low-dose hCG administration in addition to hMG in a patient with refractory hypothalamic amenorrhea. A 24-year-old woman with weight loss-related amenorrhea underwent ovulation induction and intracytoplasmic sperm injection (ICSI). Administration of exogenous gonadotropins was ineffective in ovulation induction. Supplementation with low-dose hCG in order to increase luteinizing hormone (LH) activity in the late follicular phase produced late folliculogenesis and steroidogenesis, and ovulation was then successfully induced. This report reacknowledges the critical role that LH plays cooperatively with follicle-stimulating hormone in both folliculogenesis and steroidogenesis.     

Successful pregnancy following low-dose hCG administration in addition to hMG in a patient with hypothalamic amenorrhea due to weight loss

We describe successful ovulation induction with low-dose hCG administration in addition to hMG in a patient with refractory hypothalamic amenorrhea. A 24-year-old woman with weight loss-related amenorrhea underwent ovulation induction and intracytoplasmic sperm injection (ICSI). Administration of exogenous gonadotropins was ineffective in ovulation induction. Supplementation with low-dose hCG in order to increase luteinizing hormone (LH) activity in the late follicular phase produced late folliculogenesis and steroidogenesis, and ovulation was then successfully induced. This report reacknowledges the critical role that LH plays cooperatively with follicle-stimulating hormone in both folliculogenesis and steroidogenesis.     

Prolonged dopamine receptor blockade in normoprolactinemic amenorrhea: a double-blind placebo study

Patients with functional amenorrhea may have a raised central dopaminergic activity, leading to inhibition of pituitary-ovarian function. In a double-blind placebo trial, ten patients with amenorrhea received metoclopramide (MTC) orally in daily doses from 20 to 7.5 mg in a sequential form for 10 weeks. Six patients received placebo. Serum levels for luteinizing hormone (P less than 0.02), follicle-stimulating hormone (P less than 0.05), and prolactin (P less than 0.001) increased significantly during MTC administration, and no (P greater than 0.05) hormonal changes occurred in the placebo group. Six patients observed vaginal bleedings during MTC administration but without postovulatory progesterone levels. Dopamine receptor blockade may activate the hypothalamic-pituitary axis of amenorrheic patients, although an ovulatory response is not achieved.     

Opioid regulation of luteinizing hormone in amenorrheic patients after therapy for induction of ovulation

This study evaluated the activity of central opiate receptors modulating luteinizing hormone (LH) secretion before and during treatment with human menopausal gonadotropin (n = 8) or purified human urinary follicle-stimulating hormone (n = 6) in 14 patients with hypogonadotropic hypogonadism (n = 6) or secondary amenorrhea (n = 8). LH response to saline infusion and naloxone administration (4 mg intravenously) was assessed. As control, 6 normal ovulating women were studied. Before therapy, all amenorrheic patients showed no LH increase after naloxone injection. Gonadotropin treatment restored the naloxone-induced LH response at preovulatory and midluteal phases in ovulating patients with secondary amenorrhea. The same response was present in spontaneously ovulating women but was absent in the hypogonadotropic hypogonad patients, despite the gonadotropin therapy's efficiency. In conclusion, when the alteration of gonadotropin-releasing hormone synthesis and/or release is reversible, the opioid system actively participates in the regulation of the hypothalamus-pituitary-gonadal axis.     

Induction of ovulation in amenorrheic patients with gonadotropin-releasing hormone and human menopausal gonadotropin

In five hypothalamic amenorrhea patients who underwent chronic intermittent gonadotropin-releasing hormone (GnRH) therapy for induction of ovulation, small doses (2 to 4 ampules/day) of human menopausal gonadotropin (hMG) were administered 9 to 32 days after the start of GnRH treatment. In seven treatment cycles, the addition of hMG initiated a sudden rise of 17 beta-estradiol concentrations, followed by a luteinizing hormone and follicle-stimulating hormone surge and ultrasonographic evidences of ovulation. Four of five patients conceived (singleton pregnancies) after the first or second treatment course. There were no clinical signs of ovarian hyperstimulation. Combined therapy of GnRH and hMG may be useful, therefore, for the treatment of hypothalamic amenorrhea patients who demonstrate prolonged follicular phases or luteinized unruptured follicle syndrome under chronic treatment with pulsatile GnRH alone.     

Antecedent factors and outcome in amenorrhea-galactorrhea

One hundred seventeen patients with amenorrhea and galactorrhea or hyperprolactinemia were evaluated with regard to antecedent factors, results of investigations, and management. Full details of the outcome of prolonged follow-up were available for 104 patients. Patients who developed amenorrhea-galactorrhea after withdrawal of oral contraceptives or postpartum had a lower incidence of pituitary adenomas than did those who developed amenorrhea-galactorrhea spontaneously. Six of a total of 40 tumors were detected only during the follow-up period. This study suggests that patients with spontaneous amenorrhea-galactorrhea have a greater risk of developing a detectable pituitary adenoma than do those with postpill or postpartum symptoms. However, patients with a microadenoma are more likely to have had postpill onset of hyperprolactinemia. Plasma prolactin (PRL) in patients with postpill amenorrhea-galactorrhea increased in proportion to the duration of oral contraceptive use.     

Ovulation induction and pregnancies in 100 consecutive women with hypergonadotropic amenorrhea

The efficacy of a technique of gonadotropin suppression and human menopausal gonadotropins (hMG) to induce ovulation in women with hypergonadotropic amenorrhea was evaluated in 100 consecutive women. Ovulation was achieved in 19% of cycles (68/361), the pregnancy rate per cycle was 5.2% (19/361), and the viable pregnancy rate was 2.2% (8/361). In the majority of the successful cases, estrogen was used to decrease the elevated luteinizing hormone and follicle-stimulating hormone levels, especially where the ethinyl estradiol therapy alone induced a rise in endogenous 17 beta-estradiol levels with hMG used to boost the follicle to maturation. Although the success rate is low, this technique can result in some successes in otherwise almost hopeless cases.     

Effect of dexamethasone on gonadotropin responsiveness to luteinizing hormone-releasing hormone and clomiphene in women with secondary amenorrhea.

We have studied the effects of administration of dexamethasone, 2 mg orally every 6 hours, for 5 days on the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) induced by luteinizing hormone-releasing hormone (LHRH) in six women with secondary amenorrhea and on the release of these gonadotropins induced by clomiphene citrate in 10 women with secondary amenorrhea. Dexamethasone suppressed baseline serum levels of LH and FSH and blunted the LHRH-induced release of LH and FSH in six women. Following dexamethasone administration, the LH and FSH response to clomiphene citrate, which competes for gonadal steroid receptor binding sites in the hypothalamus, resulting in increased release of LHRH, was blunted in the 10 women studied. The data indicate that short-term administration of pharmacologic doses of glucocorticoids suppresses the secretion of LH and FSH by a direct effect on the anterior pituitary and possibly by an effect at the suprahypophyseal level with inhibition of release of LHRH.     

Amenorrhea following the administration of oral contraceptives

It is estimated that about 2.2% of women experience amenorrhea and anovulatory cycles after discontinuing use of oral contraceptives (OCs), although exact figures are lacking due to differences of definition and problems of diagnosis. Several possible mechanisms to explain the occurrence of postpill amenorrhea have been suggested, including endometrial atrophy and fibrosis, changes in the ovaries similar to those found in Stein-Levanthal syndrome, hypothalamic disorder, late menarche, irregular cycles, and periods of amenorrhea before or during OC use. Previous pregnancies, duration of pill use, and formulation utilized are apparently not related to occurrence of post-pill amenorrhea. Clinical diagnosis requires detection of ovulation by means of basal body temperature, cervical mucus changes, and vaginal smears. If amenorrhea persists after administration of a progestagen to induce bleeding, more complete examinations must be done to exclude pituitary tumor, Cushing's syndrome, thyroid problems, and possible precocious menopause or anorexia nervosa. X-rays, administration of thyroid or suprarenal hormones, gonadotropins, or estrogens, an endometrial biopsy, or laparoscopy may be necessary. Generally all test values are normal except that levels of estrogens, follicle stimulating hormone, and luteinizing hormone are usually reduced. Treatment of post-pill amenorrhea can take various forms. About 5% of cases appear to resolve spontaneouusly; efforts should therefore be made to detect ovulation through basal body temperature, cervical mucus and vaginal smears. Corticosteroids including prednisone and dexametasone may administrered, or if estrogen levels are low and the patient fails to respond to progestagens with withdrawal bleeding, clomiphene may be used. Human menopausal gonadotropin or human chorionic gonadotropin can be in patients with low estrogen levels who do not respond to clomiphene. Ergocriptine derivatives may be used in cases with associated galactorrhea due to basal hyperprolactinemia. Palliative treatment with OCs may be used in patients who wish to avoid pregnancy. The prognosis is always poor in the presence of galactorrhea or if progestagen administration is not followed by withdrawal bleeding or estrogen levels are low. Treatment is usually futile in cases of polycystic ovaries that have sclerosed. The most significant feature of such amenorrhea is its role in infertility. If the patient wishes to become pregnant after some period of OC use, it is advisable to interrupt treatment periodically until 1-2 normal menstrual cycles have reappeared, especially in young patients who had irregular cycles before initiating hormonal contraception.     

The impact of luteinizing hormone in assisted reproduction: a review

PURPOSE OF REVIEW: Although the key role of luteinizing hormone in ovarian function, the promotion of follicular growth and maturation, is widely acknowledged, its usefulness as a predictor of ovarian status, and as a supplement during fertility treatment, remains controversial. RECENT FINDINGS: Luteinizing hormone alone is not an effective predictor of ovarian function. In combination with follicle-stimulating hormone, as the so-called follicle-stimulating hormone: luteinizing hormone ratio, it serves as a useful marker of ovarian status. Although published data on luteinizing hormone supplementation during ovarian hyperstimulation are somewhat limited, recent well-designed studies suggest a beneficial effect of: (1) luteinizing hormone supplementation for women with inadequate responses to follicle-stimulating hormone-only stimulation; (2) in primarily young patients with low baseline luteinizing hormone levels and, consequently, insufficient remaining endogenous luteinizing hormone concentration during pituitary suppression; and (3) in older women with higher baseline luteinizing hormone levels and age-appropriate ovarian function, who require higher luteinizing hormone thresholds, even during pituitary suppression. SUMMARY: Luteinizing hormone levels, as a component of the follicle-stimulating hormone: luteinizing hormone ratio, contribute to the assessment of ovarian function, whereas the supplementation of luteinizing hormone on an individualized basis, in carefully selected patients, improves outcomes of ovarian stimulation with gonadotropins.