Charles Faiman

Prolactin-Secreting Tumors and Hypogonadism in 22 Men

We studied 22 men with prolactin-secreting pituitary tumors and hypogonadism. Twenty complained of impotence, nine had visual impairment, and three experienced galactorrhea. None of the 17 patients undergoing operation or radiotherapy, or both, were subsequently normoprolactinemic. In all 13 patients treated with bromocryptine major clinical improvement was associated with a decrease in serum prolactin levels and in nine with an increase in serum testosterone. Two patients receiving testosterone replacement therapy showed improved potency only after bromocryptine was administered. The results indicate that hyperprolactinemia frequently induces hypogonadism in men, that bromocryptine ameliorates symptoms of disease previously unchanged by operation or radiotherapy, and that the impotence observed may not be solely the result of hypogonadism.

Pituitary-ovarian relationships preceding the menopause

Abstract Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol, and progesterone concentrations were measured in 58 ovulating women in different age groups (20 to 29, 34 to 39, 40 to 44, and 45 to 50 years) at five- to seven-day intervals through a single menstrual cycle and in 18 postmenopausal women sampled weekly five to six times. The over-all hormone patterns were similar in our premenopausal groups. However, mean serum FSH levels increased with age and significantly higher concentrations were found in the 40 to 50 year group than in the 20 to 29 year group. Serum LH levels did not show a similar rise with age, although follicular LH levels in the oldest group were higher than in the 20 to 29 year group. Prolactin and estradiol concentrations did not change with age prior to the menopause, but luteal progesterone levels were lower in the three older premenopausal groups than in the 20 to 29 year group. Postmenopausal women showed elevated FSH and LH, decreased prolactin, and negligible estradiol and progesterone levels. There was an over-all significant linear correlation between prolactin and estradiol concentrations. It appears that the menopause is preceded by several years of rising gonadotropin, predominantly FSH, levels. During this period, ovarian estrogen production appears to be maintained and ovulation continues, but luteal progesterone levels decline. It is likely that these premenopausal alterations in pituitary-ovarian relationships reflect depletion of ovarian follicles.

Pituitary-Gonadal Relations in Female Children and Adolescents

Extract: Data are provided which concern daytime levels of circulating follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol and progesterone in healthy female children and adolescents. These findings are correlated with sexual and skeletal maturation. Serum estradiol and testosterone levels were low in childhood, but rose to adult levels coincident with the appearance of secondary sexual characteristics. Serum LH levels did not rise above prepubertal levels until these characteristics were already apparent. Serum FSH levels showed a biphasic pattern with age; widely scattered values, some into the adult range, were seen in infancy. Mean FSH levels then declined throughout childhood until the onset of clinical puberty at which time they increased again to adult levels. Serum progesterone concentrations remained low (below 150 ng/100 ml) until menarche. Levels of serum progresterone which suggested possible ovulation and corpus luteum formation (over 200 ng/100 ml) were found in 9 of 30 girls who were less than 3 years postmenarchal.Speculation: The finding of high serum FSH levels in female, but not in male, infants suggests that the infantile ovary may be relatively resistant to FSH stimulation. The decline in FSH levels during early childhood may represent increasing ovarian maturation, at least in terms of ability to secrete as yet unidentified gonadotropin-inhibiting feedback substance (or substances). The onset of female puberty appears to be heralded by increasing FSH secretion; although nocturnal LH release may be characteristic of early puberty, daytime elevation of this hormone is not seen until midpuberty. The surprising finding of luteal range serum progesterone levels in many early postmenarchal girls suggests that anovulatory cycles may not be characteristic of these years. The reported relative infertility of adolescent girls may relate to factors other than ovulation (such as a short corpus luteum life-span, defects in sperm capacitation, or impaired blastocyst implantation).

ENDORPHINS AND THE REGULATION OF THE HUMAN MENSTRUAL CYCLE

In order to assess a possible influence of endogenous opioids upon gonadotrophin secretion in women, we examined the effects of i.v. administration of 10 mg naloxone, a specific opiate antagonist, in ten normal menstruating women, in thirteen women with amenorrhoea and/or hyperprolactinaemia and in two women with putative deficiency of gonadotrophin‐releasing hormone (GnRH). In thirteen subjects, a saline vehicle control study (randomized order of administration) was also performed. In the normal women, naloxone failed to elicit changes in serum gonadotrophin levels when administered during the early follicular phase of the menstrual cycle. However, significant increments of LH were observed from 30 to 165 min following naloxone administration during the late follicular phase. Similar LH responses occurred in the amenorrhoeic and hyperprolactinaemic women. There was a tendency towards a concomitant increment in FSH levels, which reached statistical significance variably from 60 to 105 min post‐naloxone. The LH response to naloxone in individual subjects showed a significant (P > 0·01) quadratic (U‐shaped) relationship to the log basal oestradiol concentration. No response to naloxone was observed in the two patients with GnRH deficiency despite a brisk response to an exogenous GnRH bolus. Taken together, these data suggest that central nervous system inhibitory opioid pathways may be involved in the regulation of LH secretion in normal women and that excessive production of endogenous opioids may play a role in the pathophysiology of some amenorrhoeic conditions.

Nonpuerperal galactorrhea and hyperprolactinemia: Clinical findings, endocrine features and therapeutic responses in 56 cases

The clinical and endocrine features, and the responses to different treatment modalities, were examined in 56 patients with galactorrhea and/or hyperprolactinemia after a two month to six year follow-up period. A pituitary adenoma was diagnosed in 17 patients. A prolactin-cell adenoma was identified histologically in eight patients. Other etiologic factors were myxedema (two patients), phenothiazine ingestion (six patients) and breast manipulation (four patients). In 27 patients, including three with abnormalities of the sella turcica, no causal factor was found, and their condition was labelled as dysfunctional in origin. Symptoms were preceded by childbirth in 11 patients and by estrogen-progestin contraception in 22; pituitary adenomas were discovered in both groups in approximately the same frequency (30%) as in the over-all study group. Aside from roentgenographic studies, as well as visual field perimetry in a few cases, a serum prolactin level above 100 ng/ml was the only indicator of a pituitary prolactin-cell adenoma. Prolactin-suppression tests (L-DOPA and 2alpha-Br-ergocryptine) were found to be of no value in discriminating between tumoral and dysfunctional conditions. No significant alterations in prolactin levels occurred after water loading irrespective of basal levels or the nature of the pathologic process. Selective pituitary tumor excision (eight patients) was followed by rapid normalization of prolactin levels and disappearance of clinical abnormalities. Conversely, after pituitary irradiation (eight patients), improvement tended to be slower. Treatment of infertility in those patients without an apparent organic lesion was more successful with 2alpha-Br-ergocryptine (three of three) than with clomiphene (two of seven). Pregnancies following the administration of drugs or after surgical treatment were uneventful. Since follow-up resulted in the early diagnosis of pituitary tumors from seven to 56 months after initial investigation, and since no diagnostic tools are currently available which help to discriminate between tumoral and dysfunctional conditions before abnormalities become evident on roentgenograms, prolonged observation of these patients remains essential.

Pituitary-gonadal function in Klinefelter syndrome before and during puberty.

ABSTRACT: Serum concentrations of follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol were determined at intervals before and during puberty in 40 individuals with Klinefelter syndrome (47,XXY karyotype), of whom 27 had been detected in neonatal cytogenetic screening programs. Prior to the appearance of secondary sexual changes, basal serum hormone concentrations and acute responses to stimulation with gonadotropinreleasing hormone and human chorionic gonadotropin were normal. The timing of the onset of clinical puberty was normal. Early pubertal boys showed initial testicular growth and normal serum testosterone levels, while serum follicle-stimulating hormone and estradiol concentrations were significantly elevated. By midpuberty, the Klinefelter subjects were uniformly hypergonadotropic and their testicular growth had ceased. Serum testosterone concentrations after age 15 remained in the low-normal adult range. Serum estradiol levels remained high, irrespective of the presence or absence of gynecomastia. Exaggerated responses to gonadotropin-releasing hormone are seen in pubertal subjects with elevated basal gonadotropin values.

Adult-onset familial adrenal 21-hydroxylase deficiency☆

Two sisters (28 and 30 years) were investigated for primary infertility and milk hirsutism. Both had normal puberty, were having regular menses and had normal female sexual characteristics. Studies revealed elevated urinary 17-ketosteroid levels (15.8, 18.8 mg/24 hours) and increased serum levels of 17-OH-progesterone (2,756, 1,121 ng/dl), 21-desoxycortisol (1,882, 1,090 ng/dl), progesterone (300, 346 ng/dl), dehydroepiandrosterone (DHA) (1,600, 1,700 ng/dl), and androstenedione (402, 366 ng/dl) and testosterone (100, 104 ng/dl), together with a slight increase in serum 11-desoxycortisol (1,180, 1,560 ng/dl). Blood pressure, serum sodium/potassium plasma renin and serum aldosterone, corticosterone, 11-desoxycorticosterone and cortisol levels were normal. The administration of ACTH caused a further increase in 21-hydroxylase precursors; the administration of dexamethasone normalized hormone levels and produced ovulatory cycles. Similar studies in two siblings were normal. The affected sisters were HLA identical and did not share any HLA antigens with their healthy siblings. The data suggest that these patients have a mild form of 21-hydroxylase deficiency which was insufficient to cause prenatal virilization. The gene for this disorder may be allelic with that for typical congenital adrenal hyperplasia.

Pituitary-ovarian interrelationships during the puerperium

Abstract This study examines and correlates serial serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (human chorionic gonadotropin) (LH [HCG]) prolactin, estradiol, and progesterone in 2 lactating (one unsuccessful) and 2 nonlactating women during the first 45 to 68 days of the puerperium. Prolactin concentrations, which were high at delivery, declined but with marked fluctuations. Over-all prolactin levels were highest in the successful lactator. LH (HCG) concentrations decreased to normal menstrual cycle values by 2 weeks. Serum FSH levels were suppressed for the first 10 to 12 days and rose rapidly to normal over the next 2 to 6 days. Estradiol and progesterone values declined to low levels during the first week following delivery. Levels of estradiol remained low in spite of rising FSH values—for one week in both nonlactating women, 12 days in the unsuccessful lactating woman, and 18 days in the successful lactating woman. The first menses observed in 2 subjects during the study were preceded by subnormal serum progesterone increments and in one case by a subnormal gonadotropin peak.

Noninvasive diagnosis of resistant ovary syndrome by ultrasonography

OBJECTIVE To compare transvaginal ultrasonographic features of the ovaries and endometrium of patients with premature ovarian failure to normally cycling women on oral contraceptives (OCs), menopausal women with an equivalent duration of amenorrhea to the premature ovarian failure group, and patients with Turners syndrome. DESIGN Transvaginal ultrasonography in groups of women with premature ovarian failure, OC, and menopause. SETTING All subjects were studied in an academic tertiary care center. PATIENTS/PARTICIPANTS Seventeen women with premature ovarian failure, 20 volunteers on OC, 20 with menopause, and 4 patients with Turners syndrome were studied. INTERVENTION None, except for OCs in the OC group only. MAIN OUTCOME MEASURES Frequency of ovarian, ovarian follicle, and endometrial visualization and their respective measurement in the three groups. RESULTS At least one ovary was visualized in 84% of the premature ovarian failure patients as compared with 95% of the OC and menopause groups and 25% of the Turner patients. Mean ovarian volume was smaller in the premature ovarian failure group as compared with the OC group but equal to that of the menopause group. In the premature ovarian failure group, 41% had follicles in their ovaries as compared with 95% in the OC group, 5% in the menopause group, and none in the Turner group. The number of follicles per ovary was significantly lower in the premature ovarian failure as compared with the OC group, whereas only one subject had a single follicle in the menopause group. Premature ovarian failure subjects with follicles had larger ovaries than those without follicles. Endometrial thickness was not different among the groups. CONCLUSION Ultrasonography may serve to identify a substantial subset (approximately 40%) of premature ovarian failure patients with ovarian follicles and potential for fertility consistent with the diagnosis of resistant ovary syndrome.

Influence of restraint and ketamine anesthesia on adrenal steroids, progesterone, and gonadotropins in rhesus monkeys.

Abstract Changes in gonadotropins, progesterone, Cortisol, DHA, and DHAS were monitored in 10 female rhesus monkeys (Days 20-23 of the menstrual cycle) subjected to cage restraint with or without ketamine anesthesia for successive venipunctures. All animals were bled without sedation for 2 hr at 30-min intervals. Then 4 of the animals were anesthetized with ketamine-HCl and bleedings in all animals were continued for an additional 2.5 hr. FSH and progesterone were not appreciably affected by either restraint technique. LH declined steadily for the duration of the bleedings (P < 0.05). Serum levels of Cortisol and the adrenal androgens increased twofold (P < 0.05). Anesthesia with ketamine had no effect on any of the six variables when compared with saline controls. Cortisol and dehydroepiandrosterone (DHA) levels tended to plateau (P < 0.01) after 2 hr in both treated and control groups. In contrast, dehydroepiandrosterone sulfate (DHAS) levels increased continuously throughout the entire study period. These data indicate that ketamine anesthesia does not alter endocrine responses to venipuncture when administered following cage restraint of conscious animals. These findings further confirm the difficulties in obtaining estimates of basal levels of hormones which are responsive to stress and suggest that the first sample may provide the best estimate.