Longterm use of marijuana has been found to cause physiological changes that can alter individual reproductive potential. The effects of marijuana depend on the dose and can include death from depression of the respiratory system. Longterm effects are however particularly hard to assess. Marijuana is absorbed rapidly and eliminated very slowly. The active principle, delta-9-tetrahidrocannabinol (delta-9-THC), is highly liposoluble and fixes to the serum proteins, passing to the lungs and liver for metabolization and to the kidneys and liver for excretion. As with estrogens, there is an enterohepatic circuit for reabsorption and elimination. 90% is eliminated in the feces, 65% within 48 hours. Because of the enterohepatic circuit and liposolubility, elimination requires 1 week for completion. The other important biotransformation of the active principle is hydroxilation; the hydroxilated derivatives are responsible for the psychoactivity of cannabis. Cannabis affects both neuroendocrine function and the germ cells. Studies on experimental animals have indicated that THC can cause a decline in the pituitary hormones follicle stimulating hormone, luteinizing hormone, and prolactin, and in the steroids progesterone, estrogen, and androgens. Human studies have shown that chronic users have decreased levels of serum testosterone. Because steroidogenesis can be restimulated with human chorionic gonadotropin, it appears that THC does not directly affect steroid production by the corpus luteum, but that its action is mediated by the hypothalamus. Because of its potent antigonadotropic action, THC is under study as an anovulatory agent. The same animal studies have shown that ovulation returns to normal 6 months after termination of use. High rates of anovulation and luteal insufficiency have been observed in women smoking marijuana at least 3 times weekly. THC accumulates in the milk. Animal studies have shown that THC depresses the enzymes necessary for lactation and causes a diminution in the volume of the mammary glands. In recent studies, significant amounts of the drug have been detected in both mothers' milk and the blood of newborns. Animal studies indicate that THC crosses the placenta, achieving concentrations in the fetus as high as those in the mother. Animal studies also demonstrated increasing frequency of abortions, intrauterine death, and declines in fetal weight. The effects were probably due to an alteration in placental function. A human study likewise showed that marijuana use during pregnancy was significantly related to poor fetal development, low birth weight, diminished size, and decreased cephalic circumference. Congenital malformations have been observed in experimental animals exposed to THC. Declines in sperm volume and count and abnormal sperm motility have been observed in chronic marijuana users. In vitro studies show that THC produces a marked degeneration of human sperm.
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.
Of all the clinical aspects of human sterility, the anovulatory cycle is undoubtedly 1 that has produced the widest range of therapuetic successes. While in other fields progress has been very slow (male sterility or tubal obstruction), ovarian pharmacoendocrinology has shown several advances over recent years. This progress is due partly to new chemicals such as urinary menopausal gonadotropins, LH-RH, and their analogues Clomiphene and Bromocriptine. Contributing further to these good results is a greater knowledge of the etiology of anovulation and a more accurate selection of cases for treatment.
